Pyrrolidinyl hydroxamic acid compounds and their production process

ABSTRACT

A compound of formula (I) ##STR1## and its pharmaceutically acceptable salt, wherein A is hydrogen or OY, wherein Y is a hydroxy protecting group; Ar is phenyl optionally substituted with one or more substituents selected from halo, hydroxy, C 1  -C 4  alkyl, C 1  -C 4  alkoxy, CF 3 , C 1  -C 4  alkoxy-C 1  -C 4  alkyloxy and carboxy-C 1  -C 4  alkyloxy; 
     X is phenyl, naphthyl, biphenyl, indanyl, benzofuranyl, benzothiophenyl, 1-tetralone-6-yl,C 1  -C 4  alkylenedioxy, pyridyl, furyl and thienyl these groups optionally being substituted with up to three substituents selected from halo, C 1  -C 4  alkyl, C 1  -C 4  alkoxy, hydroxy, NO 2 , CF 3  and SO 2  CH 3  ; and 
     R is hydrogen, C 1  -C 4  alkyl or a hydroxy protecting group. These compounds and pharmaceutical compositions containing them are useful as analgesic, anti-inflammatory, diuretic, anesthetic or neuroprotective agents, or an agent for stroke or treatment of functional bowel diseases such as abdominal pain, for the treatment of a mammalian subject, especially a human subject. Further, the present invention provides processes for producing the hydroxamic compounds of formula (I) and their intermediate compounds of the formula. ##STR2##

This application is a 371 of PCT/JP96/00820 filed Mar. 28, 1996.

TECHNICAL FIELD

This invention relates to novel hydroxamic acid derivatives and theirpharmaceutically acceptable salts, and to pharmaceutical compositionscontaining them. These compounds and compositions are useful asanalgesic, antiinflammatory, diuretic, anesthetic or neuroprotectiveagents, or an agent for treatment of stroke or functional bowel diseasessuch as abdominal pain, for the treatment of a mammalian subject,especially a human subject.

BACKGROUND ART

Opioid analgesics such as morphine are therapeutically useful, but theirusage is strictly limited because of their side effects such as drugdependency. Thus, analgesics with high usefulness and reduced tendencyto cause drug dependency are desired. Considerable pharmacological andbiochemical studies have been carried out to discover the opioidpeptides and opioid receptors, and the dicovery of the subtype of opioidreceptor such as μ, δ, κ at a peripheral nerve in a variety of species,including human, has made a beginning towards creating new analgesics.As it is thought that opioid analgesics such as morphine act as aμreceptor agonist, separating the action based on a κ-receptor agonistfrom the action based on μ-receptor agonist has been investigated.Recently κ-selective agonists have been reported from the aboveviewpoint for example, EMD-60400: A. Barber et al., Naunyn-Schmled.Arch. Pharmacol., 345 (Suppl.): Abst 456. Some of them actually havebeen studied in clinical trials (Med. Res. Rev., 12, 525 (1992)).

However, even when a selective κ-receptor agonist is employed, use ofhigh doses can give rise to side effects such as sedation. Therefore, itwould be desired to provide compounds having better agonist activitytoward opioid κ-receptor, and in particular compounds having only lowsedative activity.

BRIEF DISCLOSURE OF THE INVENTION

The present invention provides a compound of the following formula:##STR3## and the salts thereof, wherein

A is hydrogen, hydroxy or OY, wherein Y is a hydroxy prQtecting group;

Ar is phenyl optionally substituted with one or more (preferably up tothree) substituents selected from halo, hydroxy, C₁ -C₄ alkyl, C₁ -C₄alkoxy, CF₃, C₁ -C₄ alkoxy-C₁ -C₄ alkyloxy, and carboxy-C₁ -C₄ alkyloxy;

X is phenyl, naphthyl, biphenyl, indanyl, benzofuranyl, benzothiophenyl,1-tetralone-6-yl, C₁ -C₄ alkylenedioxy, pyridyl, furyl and thienyl,these groups optionally being substituted with up to three substituentsselected from halo, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, hydroxy, NO₂, CF₃ andSO₂ CH₃ ; and

R is hydrogen, C₁ -C₄ alkyl or a hydroxy protecting group.

The hydroxamic acid derivatives of the present invention of formula (I),wherein A is hydrogen or hydroxy and R is hydrogen or C₁ -C₄ alkyl,exhibit significant agonist activity toward opioid κ-receptor. Thereforethese κ agonists are particularly useful as an analgesic agent inmammals, especially humans. They are also useful as antiinflammatory,diuretic, anesthetic or neuroprotective agents, or an agent fortreatment of stroke or functional bowel diseases such as abdominal pain,for the treatment of a mammalian subject, especially a human subject.

Accordingly, the present invention also provides a pharmaceuticalcomposition useful as an analgesic, antiinflammatory, diuretic,anesthetic or neuroprotective agent, or an agent for treatment of strokeor functional bowel diseases such as abdominal pain, for the treatmentof a mammalian subject, especially a human subject, which comprises atherapeutically effective amount of a hydroxamic acid of formula (I),wherein A is hydrogen or hydroxy and R is hydrogen or C₁ -C₄ alkyl, orits pharmaceutically acceptable salt together with a pharmaceuticallyacceptable carrier.

The compounds of formula (I), wherein either or both of OY and ORrepresent a protected hydroxy group, are useful as chemicalintermediates to the κ agonist of formula (I). Typical hydroxyprotecting groups are benzyl, triphenylmethyl, tetrahydropyranyl,methoxymethyl and R¹ R² R³ Si, wherein R¹,² and R³ are each C₁ -C₆ alkylor phenyl.

A preferred group of κ agonists compounds of the present inventionconsists of the compounds of formula (1), wherein A is hydrogen orhydroxy, Ar is phenyl, X is phenyl substituted with up to threesubstituents selected from chloro, methyl and CF₃,more preferably3,4-dichlorophenyl, and R is hydrogen. The preferred configulation ofthe carbon atom to which the group Ar is atta hed is (S).

Preferred individual compounds of the invention are:

2-(3,4-Dichlorophenyl)-N-hydroxy-N-1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl!acetamide;

N-Hydroxy-N-1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl!-2-(2,3,6-trichlorophenyl)acetamide;

N-Hydroxy-N-1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl!-2-(4-trifluoromethylphenyl)acetamide;

N-Hydroxy-N-1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl!-2-(2,4,6-trimethylphenyl)acetamide;

2-(3 ,4-Dichlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide;

2-(4-Bromophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide;

N-Hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!-2-(4-trifluoromethylphenyl)acetamide;

2-(4-Chlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide;

2-(2,3-Dichlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide;

2-(2,4-Dichlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide;

2-(2,5-Dichlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide;

2-(2,6-Dichlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide;

N-Hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!-2-(2,3,6-trichlorophenyl)acetamide;

2-(3,4-Dichlorophenyl)-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide; and

2-(3,4-Dimethylphenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide.

Further, the present invention provides a compound of the formula:##STR4## and the salts thereof, wherein

A is hydrogen, hydroxy or OY, wherein Y is hydroxy protecting group;

Ar is phenyl optionally substituted with one or more substituentsselected from halo, hydroxy, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, CF₃, C₁ -C₄alkoxy-C₁ -C₄ alkyloxy, and carboxy-C₁ -C₄ alkyloxy;

R is hydrogen, C₁ -C₄ alkyl or a hydroxy protecting group.

These compounds of formula (II) can be used as intermediates to preparethe compounds of formula (I).

Further, the present invention provides processes for producing thehydroxamic compounds of formula (I) and their intermediate compounds offormula (II).

DETAILED DISCLOSURE OF THE INVENTION

The κ agonists of formula (I) of this invention can be prepared by anumbers of methods. For example, they can be readily prepared accordingto the procedure shown in Scheme (I). ##STR5##

Thus, the κ agonists compounds of formula (I), wherein A is hydrogen orhydroxy and R is hydrogen, can be prepared by reaction of a compound ofthe formula (VI) with a carboxylic acid of the formula XCH₂ COOH,followed by removal of the protecting group P, and the protecting groupin A¹ if necessary. This is a conventional acylation reaction, which canbe carried out using standard methods, well-known to those skilled inthe art. However, a convenient way of acylating a compound of formula(VI) with an acid of the formula XCH₂ COOH comprises coupling the twocompounds in the presence of a carbodiimide compound. An especiallyconvenient carbodiimide compound is1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, which issometimes referred to as water-soluble carbodiimide, or WSC. Thisreaction is carried out by contacting substantially equivalent amountsof the acid and amine with a small excess of the carbodiimide in anappropriate solvent at a temperature in the range from -30 to 100° C.,usually from 0 to 30° C. Appropriate solvents are inactive aromatichydrocarbons, ethers, halogenated hydrocarbons, especiallydichloromethane The reaction takes about 30 minutes to 24 hours, usually30 minutes to 3 hours at room temperature. The product can be isolatedand purified by standard techniques.

The protecting group P, and any protecting group in A¹, is removed bythe appropriate method for the particular protecting group chosen. Thus,a typical protecting group is benzyl. This can be removed by catalytichydrogenation. Appropriate catalysts for hydrogenation are Pd/C,Pearlman's ctalyst, Pd black, or Pd/BaSO₄, especially 10% Pd/C.

A further convenient protecting group for P and A¹ is thetetrahydropyranyl group (THP). This can be removed by acid-catalyzedhydrolysis. Appropriate acid catalysts are organic acid, inorganic acid,or Lewis acid such as AcOH, ρ-TsOH, HCl, Me₂ AlCl etc., especially HCl.

The κ agonist compounds of formula (I), wherein R is a C₁ -C₄ alkylgroup, can be prepared by alkylation of the corresponding compounds offormula (I), wherein R is hydroxy. This alkylation can be carried out bystandard methods. A particularly convenient method involves basecatalyzed alkylation using alkyl halide in the presence of phasetransfer catalyst such as tetra-n-buthylammonium hydrogen sulfate. Theintermediate hydroxylamine of the formula (VI) can be prepared from thealcohol (V), by treatment with methanesulfonyl chloride in the presenceof a base such as triethylamine followed by addition of a protectedhydroxylamine (NH₂ OP).

The alcohol (V) is obtained from the appropriate ethanolamine compound(III) and the appropriate ethane compound of the formula (IV).

The compounds of formula (III) and (IV) are either known compounds,which can be made by the known methods, or they are analogs of knowncompounds, which can be prepared by methods analogous to the knownmethods.

The intermediate compounds of formula (II) wherein Ar is substitutedphenyl can be prepared according to the procedures shown in thefollowing Scheme 2. ##STR6## (Q is, for example, halo, C₁ -C₄ alkyl, C₁-C₄ alkoxy, C₁ -C₄ alkoxy-C₁ -C₄ alkyloxy or CF₃, n=1-5, preferably 1-3)

In the above Scheme 2, a compound (VII) can be reacted with asubstituted-styrene oxide (VIII) to form a mixture of a compounds (IX)and (X). This reaction may be carried out in the absence or presence ofa reaction inert solvent (e.g., methanol (MeOH), ethanol (EtOH),isopropylalcohol, tetrahydrofuran (THF), dioxane, dimethylformamide(DMF), dimethylsulfoxide (DMSO), methylene chloride (CH₂ Cl₂), water,benzene, toluene, n-hexane, cyclohexane) at a tempe ature from -78° C.to reflux temperature of the solvent, preferably from 0° C. to 25° C.for 5 minutes to 48 hours preferably from 0.5 to 12 hours. A compound(II') can be prepared from the mixture of a compound (IX) and a compound(X) under the samq conditions as already described in Scheme 1.

According to the above procedures, R, S configuration of compounds (IX)and (X) can be selectively determined. In addition, in the aboveprocedures, 1-substitutedphenyl-1,2-ethanediol 2-tosylate can be usedinstead of the substituted-styrene oxide (VIII).

The compounds of formula (1) of this invention are basic, and thereforethey will form acid-addition salts. All such salts are within the scopeof this invention. However, it is necessary to use an acid additionsalts which is pharmaceutically-acceptable for administration to amammal. The acid-addition salts can be prepared by standard methods,e.g., by contacting the basic and acidic compounds in substantiallyequivalent proportions in water or an organic solvent such as methanolor ethanol, or a mixture thereof. The salts can be isolated byevaporation of the solvent. Typical salts which can be formed are thehydrochloride, nitrate, sulfate, bisulfate, phosphate, acetate, lactate,citrate, tartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ρ-toluenesulfonate, oxalate and pamoate (1,1'-methylene-bis-(2-hydroxy-3-naphtoate)) salts.

The compounds of formula (I) of this invention, wherin R is hydrogen,are acidic, and they will form base salts. All such salts are within thescope of this invention. However, it is necessary to use a base saltwhich is pharmaceutically-acceptable for administration to a mammal. Thebase salts can be prepared by standard methods, e.g., by contacting theacidic and basic compounds in substantially equivalent proportions inwater or an organic solvent such as nethanol or ethanol, or a mixturethereof. The salts can be isolated by evaporation of the solvent.Typical base salts which can be formed are the sodium, potassium,calcium and magnesium salts, and also salts with ammonia and amines,such as ethylamine, diethylamine, triethylamine, cyclohexylamine,piperidine and morpholine salts.

Also included within the scope of this invention are bioprecursors (alsocalled pro-drugs) of the κ agonist compounds of the formula (I). Abioprecursor of a kappa agonist of formula (I) is a chemical derivativethereof which is readily converted back into the parent compound offormula (I) in biological systems. In particular, a bioprecursor of a κagonist of formula (I) is converted back to the parent compound offormula (I) after the bioprecursor has been administered to, andabsorbed by, a mammalian subject, e.g., a human subject. For example, itis possible to make a bioprecursor of a κ agonist of the invention offormula (I) in which one or both of A and OR is hydroxy groups by makingan ester of the hydroxy group. When only one of A and OR is a hydroxygroup, only mono-esters are possible. When both A and OR are hydroxy,mono- and di-esters (which can be the same or different) can be made.Typical esters are simple alkanoate esters, such a acetate, propionate,butyrate, etc. In addition, when A or OR is a hydroxy group,bioprecursors can be made by converting the hydroxy group to anacyloxymethyl derivative (e.g., a pivaloyloxymethyl derivative) byreaction with an acyloxymethyl halide (e. g., pivaloyloxymethylchloride).

The κ agonists compounds of the present invention of formula (I) exhibitsignificant agonist activity toward opioid κ-receptor and are thususeful as analgesic, antiinflammatory, diuretic, anesthetic andneuroprotective agents, or an agent for treatment of stroke orfunctional bowel diseases such as abdominal pain, for the treatment of amammalian subject, especially a human subject. for the treatment ofmammals, especially humans in need of such agents.

The activity of the κ-agonists compounds of formula (I) of the presentinvention, is demonstrated by the opioid receptor binding activity. Suchactivity may be determined in homogenates from guinea pig whole brain adescribed by Regina, A. et al. in J. Receptor Res. 12: 171-180, 1992. Insummary, tissue homogenate is incubated at 25° C. for 30 min in thepresence of labelled ligand and test compounds. The μ-sites are labelledby 1 nM of (3H)- D Ala2,MePhe4, Gly-ol5!enkephalin (DAMGO), the δ-sitesby 1 nM of (3H)- D-Pen2,5!enkephalinDPDPE) and the κ-sites by 0.5 nM(3H)-CI-977. The non specific binding is measurd by use of 1 mM CI-977(κ), 1mM (DAMGO) (μ), 1 mM (DPDPE) (δ). Data are expressed as the IC₅₀values obtained by a non-linear fitting program using the Cheng andPrusoff equation. Some compounds prepared in the Examples showed a lowIC₅₀ value in the range of 0.01 to 100 nM.

The activity of the κ agonists Compounds can also be demonstrated by theFormalin Test as described by Wheeler-Aceto, H. et al. inPsychopharmacology 104: 35-44, 1991. In this testing, male SD rats(80-100 g) are injected s.c. with a test compound dissolved in 0.1%methyl cellulose saline or vehicle. After 30 min., 50 ml of a 2%formalin are injected into a hind paw. The number of linking theinjected paw per observation period is measured 15-30 min. after theinjection of formalin and expressed as % inhibition compared to therespective vehicle group.

The activity of the κ agonists can also be demonstrated by the RotarodTest as described by Hayes, A. G. et al. in Br. J. Pharmacol. 79:731-736, 1983. In this testing, a group of 6-10 male SD rats (100-120 g)are selected for their ability to balance on a rotating rod (diameter 9cm, rate of rotation 5 r.p.m.). The selected rats are then injected s.c.with a test compound dissolved in 0.1% methyl cellulose saline. Theanimals are tested again 30 min. after treatment; a rat falling off thebar more than twice within 150 seconds is considered to be showing motorimpairment and the animal's performance (i.e., time on the rotarod) arerecorded. The ED₅₀ value, defined as the dose of the drug which halvesthe performance time is observed in the control group.

The κ agonists compounds of formula (1) of this invention can beadministered via either the oral, parenteral or topical routes tomammals; In general, these compounds are most desirably administered tohumans in doses ranging from 0.01 mg to 50 mg per day, althoughvariations will necessarily occur depending upon the weight andcondition of the subject being treated, the disease state being treatedand the particular route of administration chosen. However, a dosagelevel that is in the range of from 0.01 mg to 1 mg per kg of body weightper day, single or devided dosage is most desirably employed in humansfor the treatment of pain in a ostoperative patient.

The compounds of the present invention may be administered alone or incombination with pharmaceutically acceptable carriers or diluents byeither of the above routes previously indicated, and such administrationcan be carried out in single or multiple doses. More particularly, thenovel therapeutic agents of the invention can be administered in a widevariety of different dosage forms i.e., they may be combined withvarious pharmaceutically acceptable inert carriers in the form oftablets, capsules, lozenges, trochees, hard candies, powders, sprays,creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrups,and the like. Such carriers include solid diluents or fillers, sterileaqueous media and various nontoxic organic solvents, etc. Moreover, oralpharmaceutical compositions can be suitably sweetened and/or flavored.In general, the therapeutically-effective compounds of this inventionare present in such dosage forms at concentration levels ranging 5% to70% by weight, preferably 10% to 50% by weight.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate,dipotassium phosphate and glycine may be employed along with variousdisintegrants such as starch and preferably corn, potato or tapiocastarch, alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often very useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in gelatine capsules; preferred materials in this connectionalso include lactose or milk sugar as well as high molecular weightpolyethylene grycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the active ingredient may be combinedwith various sweetening or flavoring agents, coloring matter or dyes,and, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various like combinations thereof.

For parenteral administration, solutions of a compound of the presentinvention in either sesame or peanut oil or in aqueous propylene glycolmay be employed. The aqueous solutions should be suitably buffered(preferably pH>8) if necessary and the liquid diluent first renderedisotonic. These aqueous solutions are suitable for intravenous injectionpurposes. The oily solutions are suitable for intra-articular,intra-muscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well-known to those skilled in theart. Additionally, it is also possible to administer the compounds ofthe present invention topically when treating inflammatory conditions ofthe skin and this may preferably be done by way of cream , jellies,gels, pastes, ointments and the like, in accordance with standardpharmace tical practice.

EXAMPLES AND PREPARATIONS

The present invention is illustrated by the following examples andpreparations. However, it should be understood that the invention is notlimited to the specific details of these examples and preparations.Melting points were taken with a Buchi micro melting point apparatus anduncorrected. Infrared Ray absorption spectra (IR) were measured by aShimazu infrared spectrometer (IR-470). ¹ H and ¹³ C nuclear magneticresonance spectra (NMR) were measured in CDCl₃ by a JEOL NMRspectrometer (JNM-GX270, 270 MHz) unless otherwise indicated and peakpositions are expressed in parts per million (ppm) downfield from tetraethylsilane. The peak shapes are denoted as follows: s, singlet; d,doublet; t, triplet; m, multiplet; br, broad.

Preparation 1 (S)-N-Benzyloxy-1-phenyl1-2-2pyrrolidinoethyanolamine

To a stirred solution of (R)-2-phenyl-2-pyrrolidinoethanol (E. Brown etal, Tetrahedron: Asymmetry, 1991, 2, 339; 4.78g, 25 mmol) andtriethylamine (3.95 ml, 28 mmol) in CH₂ Cl₂ (50 ml) was addedmethanesulfonyl chloride (2 ml, 26 mmol) dropwise at 0° C. (ice bath).After 3 h stirring at 0° C. to room temperature (rt), the reactionmixture was washed with saturated NaHCO₃ aqueous solution, dried (Na₂SO₄), and concentrated to give 5.88 g of yellow solid and brown viscousoil mixture. To this mixture was added O-benzylhydroxylamine(this wasprepared from O-benzylhydroxylamine hydrochloride 5.99 g (37.5 mmol) bybasification) and ethanol (6 ml) and the mixture was stirred at 80° C.for 1 h. The solvent was evaporated to give 9.47 g of white solid whichwas collected by filtration and washed with ethanol/ether to afford 6.96g (83.7%) of hydrochloride salt of desired product as white crystalline,mp 161-162° C.

¹ H NMR (270 MHz, CDCl₃)δ 7.44-7.25 (10 H, m), 6.40 (1 H, br.s), 4.68(1H, d, J=11.7 Hz), 4.68-4.62 (1 H, m), 4.63 (1 H, d, J=11.7 Hz),3.90-3.70 (1 H, m), 3.60 (1 H, dd, J=7.7, 13.2 Hz), 3.55-3.40 (1 H, m),3.05 (1 H, dd, J=5.5, 13.2 Hz), 2.80-2.65 (1 H, m), 2.65-2.45 (1 H, m),2.25-2.05 (2 H, m), 2.05-1.80(3 H, m). Anal. Calcd for C₁₉ H₂₄ N₂ O-HCl: C, 68.56 ; H, 7.57; N, 8.42 ; Cl, 10.65. Found : C, 68.36 ; H, 7.70 ;N, 8.39 ; Cl, 11.13.

This hydrochloride salt (80 mg) was basified with a nmonium hydroxidesolution, extracted with CH₂ Cl₂, dried (Na₂ SO₄), and concentrated togive 67 mg of free amine derivative as a colorless oil.

¹ H NMR (270 MHz, CDCl₃)δ 7.46-7.12 (10 H, m), 6.53 (1 H, br.s), 4.53 (1H, d, J=11.0 Hz), 4.45 (1 H, d, J=11.4 Hz), 4.20 (1 H, dd, J=3.7, 11.4Hz), 2.90 (1 H, dd, J=11.4, 12.5 Hz), 2.70-2.60 (2 H, m), 2.50-2.35 (2H, m), 2.28 (1 H, dd, J=4.0, 12.5 Hz), 1.80-1.70 (4 H, m).

1R(neat): 3250cm⁻¹. α!_(D) =+44.6(c=0.67, MeOH).

EXAMPLE 1 N-Benzyloxy-2-(3,4-dichlorophenyl)-N-1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl!acetamide

To a stirred solution of(S)-1-(2-O-benzylhydroxylamino-2-phenyl-ethyl)pyrrolidine hydrochloride(2.88 g, 8.65 mmol) and 3,4-dichlorophenylacetic acid (2.05 g, 10 mmol)in CH₂ Cl₂ (30 ml) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30 g, 12mmol) at room temperature. After 1 hrstirring, the reaction mixture waswashed with water and saturated NaHCO₃ aqueous solution, dried (Na₂SO₄), and concentrated to give 4.44 g of pale brown viscous oil. To thisoil was added methanol (2 ml) and stood for 1 hr. The white crystallineappeared was collected by filtration to give 1.60 g of white powder. Thefiltrate was concentrated to afford 2.84 g of oil and solid mixture,which was purified by column chromatography(silica gel; 100 g, CH₂ Cl₂/MeOH: 40/1) to give 0.82 g of clear yellow viscous oil, which wascrystallized by addition of methanol (0.2 ml).

Total yield was 2.42 g(57.9%). mp 88.5-90° C.

¹ H NMR (270 MHz, CDCl₃)δ 7.46-7.21 (12 H, m), 6.98 (1 H, dd, J=2.2, 8.4Hz), 5.80-5.65 (1 H, in), 4.73 (1 H, d, J=10.3 Hz), 4.43 (1 H, d, J=10.6Hz), 3.77 (1 H, d, J=15.8 Hz), 3.61-3.51 (2 H, m, including 1 H, d,J=15.4 Hz at 3.54 ppm), 2.75-2.60 (3 H, m), 2.55-2.40 (2 H, m),1.80-1.50 (4 H, m).

1R(Nujol): 1670 cm⁻¹.

EXAMPLE 2 2-(3.4-Dichlorophenyl)-N-hydroxy-N-1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl!acetamide

A suspension mixture of N-benzyloxy-2-(3,4-dichlorophenyl)-N-1-(S)-phenyl-2-5 (1-pyrrolidinyl)ethyl!acetamide (1.60 g, 3.3 mmol), 10%palladium on carbon (0.16 g), and HCl gas saturated methanol (20 ml) inmethanol (20 ml) was stirred under hydrogen atmosphere at roomtemperature for 13 h. After removal of the catalyst by Celitefiltration, the filtrate was concentrated to give 1.63 g of violetcolored viscous oil, which was basified with NH₄ OH and extracted withCH₂ Cl₂ (20 ml×3). The extract combined was dried (Na₂ SO₄) andconcentrated to afford a brown colored crystalline, which was collectedby filtration and washed with ether/hexane to give 1.04 g (80%) of paleyellow powder. mp 118-120° C. ¹ H NMR (270 MHz, CDCl₃)δ 7.44 (1 H, d,J=1.8 Hz), 7.37-7.24 (6 H, m, including 1 H, d, J=8.4 Hz at 7.36 ppm),7.17 (1 H, dd, J=1.8, 8.4 Hz), 5.56 (1 H, dd, J=5.9, 10.3 Hz), 3.90 (1H, d, J=14.3 Hz), 3.70 (1 H, d, J=13.9 Hz), 3.31 (1 H, dd, J=10.6, 12.5Hz), 2.73 (1 H, dd, J=5.9, 12.5 Hz), 2.60-2.45 (4 H, m), 1.80-1.55 (4 H,m).

1R(CH₂ Cl₂) 3450, 1650 cm⁻¹.

MS m/z: 394 (M⁺ +2, 0.48), 392(M⁺, 1.1), 211(4.8), 173(3.1), 149(12.9),132(12.8), 99(28.8), 84(100).

925 mg of this crystalline was dissolved in CH₂ Cl₂ (10 ml) To thissolution was added HCl gas saturated ether (10 ml) at room temperature.The mixture solution was concentrated to give a white crystalline, whichwas collected by filtration and washed with ether to afford 971 mg ofHCl salt as white powder.

mp 161-162° C.

α!_(D) =+119.8(c=0.884, MeOH).

Anal. Calcd for C₂₀ H₂₂ Cl₂ N₂ O₂.HCl.0.5H₂ O: C, 54.75; 5.51; N, 6.38

Found: C, 54.96; H, 5.49; N, 6.44.

EXAMPLE 3 2-(3 4-Dichlorophenyl)-N-methoxy-N-1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl!acetamide

A mixture of 2-(3,4-Dichlorophenyl)-N-hydroxy-N-1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl!acetamide (598 mg, 1.5 mmol),tetrabutylammonium hydrogen sulfate(10 mg), NaOH 50% aqueous solution (1ml), and iodomethane (0.12 ml, 2 mmol) in toluene (4 ml) was stirred atroom temperature for 3 h. The rhixture was extracted with ethyl acetate(20 ml×2). The extract combined was washed with brine, dried (Na₂ SO₄)and concentrated to afford 1.06 g of brown Viscous oil, which waspurified by column chromatography (silica gel 60 g, CH₂ Cl₂ /MeOH: 20/1)to give 304 mg (49.8%) of yellow viscous oil.

¹ H NMR (270 MHz, CDCl₃)δ 7.41-7.26 (7 H, m), 7.09 (1 H, dd, J=1.8, 8.1Hz), 5.70-5.60 (1 H, m), 3.83 (1 H, d, J=15.4 Hz), 3.65 (1 H, d, J=15.4Hz), 3.50 (3 H, s), 3.50 (1 H, dd, J=9.9, 12.5 Hz), 2.75-2.57 (3 H, m,including 1 H, dd, J=4.8, 12.5 Hz at 2.60 ppm), 2.55-2.40 (2 H, m), 1.70(4 H, m).

1R(neat): 1670cm⁻¹.

304 mg of this crystalline was dissolved in MeOH (5 ml). To thissolution was added HCl gas saturated ether (5 ml) at room temperature.The mixture solution was concentrated to give a white crystalline, whichwas collected by filtration and washed with ether to afford 277 mg ofHCl salt as white powder.

mp 165-166° C. Anal. Calcd for C₂₁ H₂₄ Cl₂ N₂ O₂.HCl.0.5 H₂ O: C, 55.70;5.79; N, 6.19

Found: C, 55.53; H, 5.80; N, 6.19.

EXAMPLE 4 N-Hydroxy-N-1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl!-2-(2,3,6-trichlorophenyl)acetamide

This was prepared from(S)-1-(2-O-benzylhydroxylamino-2-phenylethyl)pyrrolidine in 68% yieldaccording to a procedure similar to that described in Examples 2 and 3.

mp 217-218.5° C. (HCl salt)

¹ H NMR (270 MHz, free amine, CDCl₃)δ 7.44-7.20 (8 H, m), 5.61 (1 H, dd,J=5.9, 10.6 Hz), 4.36 (1 H, d, J=16.9 Hz), 4.26 (1 H, d, J=7.2 Hz), 3.40(1 H, dd, J=10.6, 12.5 Hz), 2.80 (1 H, dd, J=5.9, 12.5 Hz), 2.76-2.55 (4H, m), 1.90-1.70 (4 H, m).

1R(neat, free amine): 1650 cm⁻¹.

Anal. Calcd for C₂₀ H₂₁ Cl₃ N₂ O₂.HCl.0.5H₂ O: C, 50.76; 4.90; N, 5.92

Found: C, 50.58; H, 4.65; N, 5.83.

EXAMPLE 5 N-Hydroxy-N-1(S)-phenyl-2-(1-pyrrolidinyl)ethyl!-2-(4-trifluoromethylphenyl)acetamide

This was prepared from(S)-1-(2-O-benzylhydroxylamino-2-phenylethyl)pyrrolidine in 66.6% yieldaccording to a procedure similar to that described in Examples 2 and 3.

mp 172.8-177° C. (HCl salt)

¹ H NMR (270 MHz, free amine, CDCl₃)δ 7.55 (2 H, d, J=8.4 Hz), 7.45 (2H, d, J=8.1 Hz), 7.40-7.20 (6 H, m), 5.57 (1 H, dd, J=5.9, 10.3 Hz),4.00 (1 H, d, J=13.9 Hz), 3.81 (1 H, d, J=13.9 Hz), 3.30 (1 H, dd,J=10.6, 12.5 Hz), 2.71 (1 H, dd, J=5.9, 12.5 Hz), 2.60-2.40 (4 H, m),1.80-1.50 (4 H, m).

1R(neat, free amine): 3150, 1650 cm⁻¹.

Anal. Calcd for C₂₁ H₂₃ F₃ N₂ O₂.HCl.H₂ O: C, 56.44; 5.86; N, 6.27

Found: C, 56.16; H, 5.77; N, 6.76.

EXAMPLE 6 N-Hydroxy-2-(1-naphthyl)-N-1-(S)-Phenyl-2-(1-pyrrolidinyl)ethyl!acetamide

This was prepared from(S)-1-(2-O-benzylhydroxylamino-2-phenylethyl)pyrrolidine in 65.1% yieldaccording to a pro edure similar to that described in Examples 2 and 3.

mp 81.0-83.5° C. (HCl salt)

¹ H NMR (270 MHz, free amine, CDCl₃)δ 7.55-7.20 (13 H, m), 5.59 (1 H,dd, J=5.9, 10.3 Hz), 4.43 (1 H, d, J=14.7 Hz), 4.10 (1 H, d, J=15.0 Hz),3.31 (1 H, dd, J=11.0, 12.1 Hz), 2.65 (1 H, dd, J=5.9, 12.5 Hz),2.55-2.35 (4 H, m), 1.60-1.35 (4 H, m).

1R(neat, free amine): 3150, 1650 cm⁻¹.

Anal. Calcd for C₂₄ H₂₆ N₂ O₂.HCl.1.2H₂ O: C, 66.64; 6.85; N 6.48

Found: C, 66.93; H, 6.50; N, 6.02.

EXAMPLE 7 N-Hydroxy-N-1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl!-2-(2,4,6-trimethylphenyl)acetamide

This was prepared from(S)-1-(2-O-benzylhydroxylamino-2-phenylethyl)pyrrolidine in 58.9% yieldaccording to a pro edure similar to that described in Examples 2 and 3.

mp 186-187.2° C. (HCl salt).

¹ H NMR (270 MHz, free amine, CDCl₃)δ 7.42-7.24 (6 H, m), 6.82 (2 H, s),5.70-5.55 (1 H, m), 3.86 (2 H, br.s), 3.38 (1 H, dd, J=10.6, 12.1 Hz),2.74 (1 H, dd, J=5.9, 12.5 Hz), 2.70-2.55 (4 H, m), 2.22 (9 H, s),1.85-1.75,(4 H, m).

1R(neat, free amine): 3220, 1640 cm⁻¹.

Anal. Calcd for C₂₃ H₃₀ N₂ O₂ HCl.1.3H₂ O: C, 64.79; 7.94; N, 6.57

Found: C, 64.51; H, 7.48; N, 6.31.

EXAMPLE 8 N-Hydroxy-2-(4-pyridyl)-N-1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl!acetamide

This was prepared from(S)-1-(2-O-benzylhydroxylamino-2-phenylethyl)pyrrolidine in 67.9% yieldaccording to a procedure similar to that described in Examples 2 and 3.

¹ H NMR (270 MHz, free amine, CDCl₃)δ 8.46 (2 H, d, J=5.9 Hz), 7.40-7.18(8 H, m), 5.61 (1 H, dd, J=5.5, 10.6 Hz), 3.91 (1 H, d, J=14.3 Hz), 3.77(1 H, d, J=13.9 Hz), 3.33 (1 H, dd, J=11.0, 12.1 Hz), 2.68 (1 H, dd, J5.5, 12.5 Hz), 2.57-2.40 (4 H, m), 1.80-1.55 (4 H, m).

1R(neat, free amine): 1640 cm⁻¹.

EXAMPLE 9 2-Benzo b!furan-4-yl)-N-hydroxy-N-1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl!acetamide

This was prepared fro in(S)-1-(2-O-benzylhydroxylamino-2-phenylethyl)pyrrolidine in 73.5% yieldaccording to a procedure similar to that described in Examples 2 and 3.

¹ H NMR (270 MHz, CDCl₃)δ 7.59 (1 H, d, J=1.8 Hz), 7.45-7.20 (9 H, m),6.98 (1 H, br.s), 5.58 (1 H, dd, J=5.9, 10.6 Hz), 4.24 (1 H, d, J=13.6Hz), 3.91 (1 H, d, J=13.6 Hz), 3.28 (1 H, dd, J=11.3, 11.7 Hz), 2.60 (1H, dd, J=5.9, 12.5 Hz), 2.45-2.30 (4 H, m), 1.60-1.30 (4 H, m).

1R(neat, free amine): 1650 cm⁻¹.

PREPARATION 2 1.4-Diiodo-2-(S)-(tetrahydropyranyloxy)butane

To a stirred solution of (S)-(-)-1,2,4-butanetriol (10.61 g, 0.1 mol) inpyridine (100 ml) was added p-toluenesulfonyl chloride (38.13 g, 0.2mol) by portions at 0° C. After 2 h stirring, the reaction mixture waspoured into 10% HCl aqueous solution including ice and acidified to pH2.The mixture was extracted with ethyl acetate (150 ml×3). The extractcombined was washed with brine, dried (Na₂ SO₄), and concentrated togive 42.88 g of colorless oil. A mixture of this crude ditosylate (42.88g, 0.1 mol) and NaI(44.97 g, 0.3 mol) in acetone (300 ml) was refluxedwith stirring for 5 h. The solid precipitated was removed by filtrationand the filtrate was concentrated. The residue was dissolved in ethylacetate and washed with Na₂ S₂ O₃ aqueous solution and brine. After dry(Na₂ SO₄), the solvent was evaporated and the residue was purified bycolumn chromatography (silica gel 250 g, hexane/ethyl acetate: 10/1) toafford 24.81 g of colorless oil. A mixture of this oil (24.81 g, 76.1mmol), 3,4-dihydro-2 H-pyran (21.9 ml, 0.24 mol), and pyridiniump-toluene ulfonate (125 mg) in CH₂ C₂ (100 ml) was stirred at roomtemperature for 12 h. The reaction mixture was diluted with CH₂ Cl₂ (100ml), washed with NaHCO₃ aqueous solution, and dried (Na₂ SO₄).Evaporation of the solvent gave 33.56 g of pale yellow oil, which waspurified by column chromato-graphy (silica gel 250 g, hexane/ethylacetate: 20/1) to afford 28.75 g (70.1% for 3 steps) of colorless oil.

¹ H NMR (270 MHz, CDCl₃)δ 4.80-4.75 (1 H, m), 4.02-3.85 (1 H, m),3.70-3.17 (6 H, m), 2.27-2.01 (2 H, m), 1.90-1.55 (6 H, m).

PREPARATION 32-(R)-Phenyl-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethanol

A suspension mixture of 1,4-diiodo-2-(S)-(tetrahydropyranyloxy)-butane(12.50 g, 30 mmol), R-(-)-phenyolglycinol (3.43 g, 25 mmol), and K₂ CO₃(6.91 g, 50 mmol) in ethanol (50 ml) was refluxed with stirring for 6 h.The white solid was removed by filtration and the filtrate wasconcentrated. The residue was diluted with NaHCO₃ aqueous solution (30ml) and extracted with CH₂ Cl₂ (20 ml×3). After dry (Na₂ SO₄), thesolvent was evaporated to give 9.54 g of clear yellow oil, which waspurified by column chromatography (silica gel 150 g, CH₂ Cl₂ /MeOH:20/1) to afford 7.22 g (99%) of colorless viscous oil.

¹ H NMR (270 MHz, CDCl₃)δ 7.37-7.27 (5 H, m), 4.61-4.51 (1 H, m),4.40-4.28 (1 H, m), 3.91-3.75 (3 H, m), 3.55-3.42 (2 H, m), 2.92-2.72 (1H, m), 2.70-2.57 (2 H, m), 2.55-2.25 (2 H, m), 2.20-1.95 (1 H, m),1.93-1.60 (3 H, m), 1.60-1.45 (4 H, m).

1R(neat): 3450 cm⁻¹.

PREPARATION 41-(S)-Phenyl-N-tetrahydropyranyloxy-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1yl)ethylamine

This was prepared from 2-(R)-phenyl-2-(3-(S)-tetrahydro-pyranyloxypyrrolidin-1-yl)ethanol andO-tetrahydropyranyl-hydroxylamine (R. N. Warrener and E. N. Cain, Angew.Chem. Int. Edit. 1966, 5, 511) in 42.5% yield as a brown oil accordingto a procedure similar to that described in Preparation 1.

¹ H NMR (270 MHz, CDCl₃)δ 7.45-7.25 (5 H, m), 6.51 (1 H, br.s),4.80-4.73 (1 H, m), 4.65-4.55 (1 H, m), 4.45-4.33 (1 H, m), 4.28-4.15 (1H, m), 4.00-3.75 (2 H, m), 3.70-2.55 (9 H, m), 2.30-2.05 (1 H, m),1.90-1.35 (12 H, m).

EXAMPLE 10 2-(3,4-Dichlorophenyl)-N-tetrahydropyranyloxy-N-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was prepared from1-(S)-Phenyl-N-tetrahydropyranyloxy-2-(3-(S)-tetrahydropyranyloxypyrroidin-1-yl)ethylamineand 3,4-dichlorophenylacetic acid in 69.8% yield as a clear brownViscous oil according to a procedure similar to that described inExample 1.

¹ H NMR (270 MHz, CDCl₃)δ 7.43-7.15 (7.4 H, m), 6.98-6.91 (0.6 H, m),5.69 (0.4 H, dd, J=4.0, 11.0 Hz), 5.58 (0.6 H , dd, J=4.8, 11.4 Hz),5.35-5.20 (1 H, m), 4.65-4.53 (1 H, m), 4.41-4.21 (1 H, m), 4.15-3.80 (4H, m), 3.68-3.10 (4 H, m), 3.03-2.80 (2 H, m), 2.70-2.35 (3 H, m),2.20-1.10 (13 H, m).

1R(neat): 1660 cm⁻¹.

EXAMPLE 11 2-(3,4-Dichlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

A mixture of 2-(3,4-Dichlorophenyl)-N-tetrahydropyranyloxy-N-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide(1.13 g, 1.96 mmol) and HCl gas saturated MeOH (4 ml) in MeOH (20 ml)was stirred at room temperature for 7 h. The solvent was evaporated. Theresidue was basified with saturated NaHCO₃ aqueous solution, extractedwith CH₂ Cl₂, and dried (Na₂ SO₄). Evaporation of the solvent gave 0.80g of brown viscous oil, which was crystallized by adding ether andscratching. The crystalline was collected by filtration and washed withether to afford 377 mg(47.1%) of white powder.

mp 98.5-99.5° C.

¹ H NMR (270 MHz, CDCl₃)δ 7.45-7.20 (7 H, m), 7.14 (1 H, dd, J=1.8, 9.9Hz), 5.62 (1 H, dd, J=5.5, 11.0 Hz), 5.00-3.00 (2 H, almost flat br.s),4.35-4.25 (1 H, m), 3.85 (1 H, d, J=14.3 Hz), 3.73 (1 H, d, J=13.9 Hz),3.38 (1 H, dd, J=11.0, 12.5 Hz), 2.95 (1 H, dt, J=5.1, 8.8 Hz), 2.73 (1H, d, J=10.6 Hz), 2.65 (1 H, dd, J=5.5, 12.5 Hz), 2.51 (1 H, dd, J=5.5,10.6 Hz), 2.40-2.27 (1 H, m), 2.22-2.07 (1 H, m), 1.65-1.50 (1 H, m).

1R(Nujol): 3070, 1640 cm⁻¹.

MS m/z: 412(M⁺ +4, 10.3), 410(M⁺ +2, 85.7), 408(M⁺, 100), 304(8.6),149(50.2), 114(22.7), 112(24.2). α!_(D) =+102.9(c=0.516, MeOH).

HCl salt: mp 65.5-67.0° C.

Anal. Calcd for C₂₀ H₂₂ Cl₂ N₂ O₃.HCl.0.5H₂ O: C, 52.82; H, 5.32; N,6.16.

Found: C, 53.09; H, 5.29; N, 6.17

PREPARATION 5 (R)-(-)-2-(4-Fluorophenyl)glycinol

This was prepared from 4-fluoro-D-a-phenylglycine in 8% yield accordingto the procedure of D. A. Evans (Organic Synthesis, 68, 77).

¹ H NMR (270 MHz, CDCl₃)δ 7.30 (2 H, dd, J=5.5, 8.4 Hz), 7.03 (2 H, t,J=8.4 Hz), 4.05 (1 H, dd, J=4.4, 8.1 Hz), 3.71 (1 H, dd, J=4.4, 10.6Hz), 3.53 (1 H, dd, J=8.4, 10.6 Hz), 2.19 (3 H, br.s).

1R(KBr): 3350, 3280 cm⁻¹.

PREPARATION 62-(R)-(4-Fluorophenyl)-2-(3-(S)-tetrahydrophyranyloxypyrrolidin-1-yl)ethanol

This was prepared from (R)-(-)-2-(4-fluorophenyl)glycinol in 68.8% yieldaccording to a procedure similar to that described in Preparaton 3.

¹ H NMR (270 MHz, CDCl₃)δ 7.31-7.26 (2 H, m), 7.03 (2 H, dd, J=8.4, 8.8Hz), 4.65-4.51 (1 H, m), 4.40-4.27 (1 H, m), 3.90-3.75 (3 H, m),3.55-3.40 (2 H, m), 2.90-2.70 (1 H, m), 2.70-2.50 (2 H, m), 2.50-2.35 (1H, m), 2.30-1.95 (2 H, m), 1.95-1.60 (3 H, m), 1.60-1.45 (4 H, m).

1R(neat): 3450 cm⁻¹.

EXAMPLE 12 2-(3,4-Dichlorophenyl)-N-1-(S)-(4-fluorophenyl)ethyl-2-(3-(S)-hydroxypyrrolidin-1-yl)!-N-hydroxyacetamide

This was prepared from2-(R)-(4-fluorophenyl)-2-3-(S)-tetrahydropyranyl-oxypyrrolidin-1-yl)ethanoland 3,4-dichlorophenylacetic acid in 52.8% yield according to aprocedure similar to that described in Preparation 4, Examples 10 and11.

¹ H NMR (270 MHz, CDCl₃)δ 7.41-7.26 (4 H, m), 7.12 (1 H, dd, J=1.8, 8.1Hz), 6.99 (2 H, dd, J=8.4, 8.8 Hz), 5.60 (1 H, dd, J=5.1, 11.0 Hz),4.35-4.25 (1 H, m), 3.82 (1 H, d, J=13.9 Hz), 3.72 (1 H, d, J=14.3 Hz),3.71 (1 H, s), 3.58 (1 H, s), 3.35 (1 H, dd, J=11.7, 12.1 Hz), 3.00-2.90(1 H, m), 2.73 (1 H, br.s, J=11.0 Hz), 2.58 (1 H, dd, J=5.1, 12.5 Hz),2.51 (1 H, dd, J=5.5, 10.6 Hz), 2.38-2.10 (2 H, m), 1.65-1.55 (1 H, m).

1R(neat): 3200, 1640 cm⁻¹.

MS m/z: 426(M⁺).

HCl salt: amorphous solid.

Anal. Calcd for C₂₀ H₂₁ Cl₂ FN₂ O₃.HCl.0.7H₂ O: C, 50.43; H, 4.95; N,5.88.

Found: C, 50.80; H, 4.96; N, 5.45.

EXAMPLE 13 2-(4-Bromophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was prepared from 2-(R) -phenyl-2- (3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethanol and 4-bromophenylaceticacid in 44.6% yield according to a procedure similar to that describedin Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.50-7.14 (9 H, m), 5.61 (1 H, dd, J=5.1, 11.0Hz), 4.28-4.22 (1 H, m), 3.90 (1 H, d, J=13.6 Hz), 3.70 (1 H, d, J=13.9Hz), 3.33 (1 H, dd, J=11.0, 12.5 Hz), 2.92-2.82 (1 H, m), 2.72-2.64 (2H, m), 2.50 (1 H, dd, J=5.5, 10.6 Hz), 2.38-2.28(1 H, m), 2.20 (2 H,br.s), 2.16-2.01 (1 H, m), 1.60-1.50 (1 H, m).

1R(neat): 3200, 1630 cm⁻¹.

MS m/z: 418(M⁺).

HCl salt: amorphous solid.

Anal. Calcd for C₂₀ H₂₃ BrN₂ O₃.HCl.0.5H₂ O: C, 51.68; H, 5.42; N, 6.03.

Found: C, 51.75; H, 5.51; N, 5.71

EXAMPLE 14 2-(3-Bromophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was prepared from2-(R)-phenyl-2(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethanol and3-bromophenylacetic acid in 29.8% yield accor ing to a procedure similarto that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.51-7.15 (9 H, m), 5.62 (1 H, dd, J=5.5, 11.0Hz), 4.28-4.20 (1 H, m), 3.94 (1 H, dd, J=13.9 Hz), 3.70 (1 H, d, J=13.6Hz), 3.35 (1 H, dd, J=11.4, 12.5 Hz), 2.92-2.83 (1 H, m), 2.70-2.62 (2H, M), 2.51 (1 H, dd, J=5.1, 10.6 Hz), 2.42 (2 H, br.s), 2.38-2.28 (1 H,m), 2.18-2.03 (1 H, m), 1.60-1.46 (1 H, m).

1R(neat): 3200, 1630 cm⁻¹.

MS m/z: 418(M⁺).

HCl salt: amorphous solid.

Anal. Calcd for C₂₀ H₂₃ BrN₂ O₃.HCl.H₂ O: C, 50.70; H, 5.53; N, 5.91.

Found: C, 50.57; H, 5.58; N, 5.90.

EXAMPLE 15 2-(4-Fluorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was prepared from 2-(R)-phenyl-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethanol and4-fluorophenylacetic acid in 23.6% yield according to a proceduresimilar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.40-7.22 (7 H, m), 7.10-6.95 (2 H, m),5.67-5.61 (1 H, m), 4.34-4.22 (1 H, m), 3.92 (1 H, d, J=13.6 Hz), 3.73(1 H, d, J=13.9 Hz), 3.36 (1 H, dd, J=10.6, 12.5 Hz), 2.96-2.86 (1 H,m), 2.76-2.62 (2 H, m), 2.58-2.48 (1 H, m), 2.40-2.28 (1 H, m),2.24-1.70 (3 H, m), 1.64-1.48 (1 H, m).

1R(neat): 3400, 1630 cm⁻¹.

MS m/z: 358(M⁺).

HCl salt: amorphous solid.

Anal. Calcd for C₂₀ H₂₃ FN₂ O₃.HCl.0.4H₂ O: C, 59.74; H, 6.22; N, 6.97.

Found: C, 59.81; H, 6.43; N, 6.88.

EXAMPLE 16 2-(3,4-Dimethoxyphenyl)-N-hydroxy-N-2,3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was prepared from2-(R)-phenyl-2-(3-(S)-tetraliydropyranyloxypyrrolidin-1-yl)ethanol and3,4-dimethoxyphenylacetic acid in 10.6% yield according to a proceduresimilar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.40-7.22 (5 H, m), 6.95-6.78 (3 H, m),5.70-5.60 (1 H, m), 4.25-4.15 (1 H, m), 3.91 (1 H, d, J=13.9 Hz), 3.88(3 H, s), 3.87 (3 H, s), 3.68 (1 H, d, J=13.9 Hz), 3.33 (1 H, dd,J=11.4, 11.7 Hz), 2.90-2.78 (1 H, m), 2.74-2.60 (2 H, m), 2.47 (1 H, dd,J=5.1, 10.6 Hz), 2.34-2.20 (1 H, m), 2.14-1.98 (1 H, m), 1.90 (2 H,br.s), 1.50-1.36 (1 H, m).

1R(neat): 3400, 1640 cm⁻¹.

MS m/z: 400(M⁺).

HCl salt: amorphoLLs solid.

Anal. Calcd for C₂₂ H₂₈ N₂ O₅.HCl.2.7H₂ O: C, 54.42; H, 7.14; N, 5.77.

Found: C, 54.31; H, 6.77; N, 5.92.

EXAMPLE 17 N-Hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!-2-(3-trifluoromethylphenyl)acetamide

This was prepared from2-(R)-phenyl-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethanol and3-trifluoromethylphenylacetic acid in 18.9% yield according to aprocedure similar to that described in Preparation 4, Examples 10 and11.

¹ H NMR (270 MHz, CDCl₃)δ 7.60-7.26 (9 H, m), 5.75-5.65 (1, m),4.35-4.25 (1 H, m), 3.99 (1 H, d, J=14.3 Hz), 3.86 (1 H, d, J=14.3 Hz),3.54-3.38 (1 H, m), 3.04-2.94 (1 H, m), 2.84-2.40 (6 H, in), 2.20-2.06(1 H, 1.70-1.55 (1 H, m).

1R(neat): 3350, 1630 cm⁻¹.

MS m/z: 408(M⁺ H)⁺.

HCl salt: amorphous solid.

Anal. Calcd for C₂₁ H₂₃ F₃ N₂ O₃.HCl.1.9H₂ O: C, 54.70; H, 5.64; N,6.08.

Found: C, 54.83; H, 5.97; N, 6.21.

EXAMPLE 18 N-Hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!-2-(4-trifluoromethylphenyl)acetamide

This was prepared from2-(R)-phenyl-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethanol and4-tritluorornetlylpllenylacetic acid in 35.4% yield according to aprocedure similar to that described in Preparation 4, Examples 10 and11.

¹ H NMR (270 MHz, CDCl₃)δ 7.56 (2 H, d, J=8.1 Hz), 7.44 (2 H, d, J=8.1Hz), 7.33-7.26 (5 H, m), 5.65 (1 H, dd, J=5.9, 11.0 Hz), 4.35-4.20 (1 H,m), 3.99 (1 H, d, J=14.3 Hz), 3.85 (1 H, d, J=13.9 Hz), 3.41 (1 H, dd,J=12.1, 12.5 Hz), 3.00-2.90 (1 H, m), 2.82-2.02 (7 H, m), 1.64-1.50 (1H, m).

1R(neat): 3100, 1650 cm⁻¹.

MS m/z: 408(M⁺).

HCl salt: mp 142.5-144.2° C.

Anal. Calcd for C₂₁ H₂₃ F₃ N₂ O₃.HCl.0.2H₂ O: C, 56.24; H, 5.48; N,6.25.

Found: C, 56.27; H, 5.61; N, 6.08.

EXAMPLE 19 2-(4-Biphenyl)-N-hydroxy-N-2(3-(S)-hydroxypyrrolidin-1-yl)1-(S)-phenylethyl!acetamide

This was prepared from 2-(R)-plenyl-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethanol and4-biphenylacetic acid in 38.8% yield according to a procedure similar tothat described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.60-7.26 (14 H, m), 5.66 (1 H, dd, J=5.1,11.0 Hz), 4.20-4.14 (1 H, m), 4.04 (1 H, d, J=13.6 Hz), 3.76 (1 H, d,J=13.2 Hz), 3.35 (1 H, dd, J=10.3, 13.6 Hz), 2.90-2.80 (1 H, m),2.73-2.63 (2 H, m), 2.55-2.45 (1 H, m), 2.35-2.22 (1 H, m), 2.10-1.96 (1H, m), 1.90 (2 H, br.s), 1.50-1.35 (1 H, m).

MS m/z: 417(M⁺ H)⁺.

HCl salt: 163.8-165.5° C.

Anal. Calcd for C₂₆ H₂₈ N₂ O₃.HCl.0.5 H₂ O: C, 67.60; H, 6.55; N, 6.06.

Found: C. 67.77; H, 6.42; N, 5.76.

EXAMPLE 20 N-Hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!-2-(4-nitrophenyl)acetamide

This was prepared from2-(R)-phenyl-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethanol and4-nitrophenylacetic acid in 11.6% yield according to a procedure similarto that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 8.14 (2 H, d, J=8.8 Hz), 7.44 (2 H, d, J=8.8Hz), 7.35-7.16 (5 H, m), 5.74 (1 H, dd, J=4.8, 10.3 Hz), 4.46-4.38 (1 H,m), 4.03 (1 H, d, J=15.0 Hz), 3.96 (1 H, d, J=15.0 Hz), 3.64-3.50 (1 H,m), 3.20-3.10 (1 H, m), 2.96 (1 H, br.d, J=10.3 Hz), 2.90-2.74 (3 H, m),2.66 (2 H, br.s), 2.30-2.16 (1 H, m), 1.84-1.70 (1 H, m).

1R(neat): 3400, 1630 cm⁻¹.

MS m/z: 385(M⁺).

HCl salt: amorphotis solid.

Anal. Calcd for C₂₀ H₂₃ N₃ O₅.HCl.5H₂ O: C, 53.51; H, 6.06; N, 9.36.

Found: C, 53.71; H, 6.01; N, 9.11

EXAMPLE 21 N-Hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!-2-(3-nitrophenyl)acetamide

This was prepared from 2 -(R )-phenyl-2 -(3 -(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethanol and 3-nitrophenylaceticacid in 11.6% yield according to a procedure similar to that describedin Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 8.17-8.08 (2 H, m), 7.66-7.20 (7 H, m), 5.64(1 H, dd, J=5.9, 11.0 Hz), 4.38-4.30 (1 H, m), 4.03 (1 H, d, J=14.7 Hz),3.90 (1 H, d, J=14.3 Hz), 3.50-3.38 (1 H, m), 3.06-2.94 (1 H, m),2.84-2.70 (2 H, m), 2.66-2.56 (1 H, m), 2.50-2.32 (1 H, m), 2.20-2.04 (1H, m), 1.96 (2 H, br.s), 1.70-1.50 (1 H, m).

MS m/z: 386(M⁺ H)⁺.

HCl salt: mp 154.3-155.5° C.

Anal. Calcd for C₂₀ H₂₃ N₃ O₃.HCl.0.3H₂ O: C, 56.22; H, 5.8); N, 9.83.

Found: C, 56.29; H, 5.80; N, 9.55.

EXAMPLE 22 2-(4- Chlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was prepared from 2-(R)-phenyl-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethanol and4-chlorophenylacetic acid in 49.4% yield according to a proceduresimilar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.40-7.20 (9 H, m), 5.65 (1 H, d, J=5.1, 11.0Hz), 5.00-3.30 (2 H, wide spread br.s), 4.35-4.25 (1 H, m), 3.86 (1 H,d, J=13.9 Hz), 3.74 (1 H, d, J=13.9 Hz), 3.40 (1 H, dd, J=11.7, 12.1Hz), 3.02-2.90 (1 H, m), 2.75 (1 H, br.d, J=10.6 Hz), 2.61 (1 H, dd,J=5.1, 12.5 Hz), 2.51 (1 H, dd, J=5.1, 10.3 Hz), 2.40-2.25 (1 H, m),2.23-2.08 (1 H, m), 1.65-1.50 (1 H, m).

1R(neat): 3400, 1630 cm⁻¹.

MS m/z: 374(M⁺).

HCl salt: mp 146.5-147.3° C.

Anal. Calcd for C₂₀ H₂₃ ClN₂ O₃.HCl.0.3H₂ O: C, 57.64; H, 5.95; N, 6.72.

Found: C, 57.87; H, 5.88; N, 6.78.

EXAMPLE 23 2-(3-Chlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was preparedfrom2-(R)-phenyl-2-(3-(S)-tetrahydropranyloxypyrrolidin-1-yl)ethanol and3-chlorophenylacetic acid in 29.6% yield according to a proceduresimilar to that described in Preparation 4, Examples 10 and 11

¹ H NMR (270 MHz, CDCl₃)δ 7.34-7.20 (9 H, m), 5.75-5.62 (1 H, m),4.35-4.25 (1 H, m), 3.94 (1 H, d, J=13.9 Hz), 3.74 (1 H, d, J=13.9 Hz),3q45 (1 H, dd, J=9.5, 12.1 Hz), 3.05-2.92 (1 H, M), 2.80 (1 H, br.d,J=10.6 Hz), 2.77-2.30 (3 H, m), 3.80-2.30 (2 H, almost flat peak),2.23-2.06 (1 H, m), 1.68-1.54 (1 H, m).

1R(neat): 3350, 1630 cm⁻¹.

MS m/z: 374(M⁺).

HCl salt: mp 113.2-114.3° C.

Anal. Calcd for C₂₀ H₂₃ ClN₂ O₃.HCl.0.4H₂ O: C, 57.40; H, 5.97; N, 6.69.

Found: C, 57.79; H, 5.84; N, 6.74.

EXAMPLE 24 2-(2-Chlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was prepared from2-(R)-phenyl-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethanol and2-chlorophenylacetic acid in 31.2% yield according to a proceduresimilar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.45-7.16 (9 H, m), 5.85-5.70 (1 H, m),4.44-4.34 (1 H, m), 4.14 (1 H, d, J=16.1 Hz), 3.91 (1 H, d, J=16.1 Hz),3.68-3.48 (1 H, m), 3.24-3.10 (1 H, m), 2.98-2.40 (6 H, m), 2.34-2.18 (1H, m), 1.86-1.70(1 H, m).

1R(neat): 3400, 1640 cm⁻¹.

MS m/z: 374(M⁺).

HCl salt: mp 146 ° C.

Anal. Calcd for C₂₀ H₂₃ ClN₂ O₃.HCl.H₂ O: C, 55.95; H, 6.10; N, 6.52.

Found: C, 56.18; H, 6.00; N, 6.55.

EXAMPLE 25 N-Hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was prepared from 2-(R)-phenyl-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethanol and2,3,5-trichlorophenylacetic acid in 51.6% yield ac ording to a proceduresimilar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl3)δ 7.45-7.26 (6 H, m), 7.14 (1 H, d, J=2.2 Hz),5.70 (1 H, dd, J=4.8, 11.0 Hz), 4.48-4.30 (1 H, m), 4.20-3.00 (2 H, widespread br.s), 4.06 (1 H, d, J=16.5 Hz), 3.90 (1 H, d, J=16.1 Hz), 3.50(1 H, dd, J=11.4, 12.1 Hz), 3.20-3.10 (1 H, m), 2.86 (1 H, br.d, J=10.3Hz), 2.75-2.60 (2 H, m), 2.55-2.35 (1 H, m), 2.35-2.20 (1 H, m),1.85-1.70 (1 H, m).

1R(neat): 3400, 1640 cm⁻¹.

MS m/z: 444(M⁺).

HCl salt: amorphous solid.

Anal. Calcd for C₂₀ H₂₁ Cl₃ N₂ O₃.HCl.H₂ O: C, 48.21; H, 4.86; N, 5.62.

Found: C, 48.56; H, 5.17; N, 5.40.

EXAMPLE 26 N-Hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!-2-(2,4,6-trichlorophenyl)acetamide

This was prepared from 2-(R)-phenyl -2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethanol and2,4,6-trichloroplienylacetic acid in 14.0% yield according to aprocedure similar to that described in Preparation 4, Examples 10 and11.

¹ H NMR (270 MHz, CDCl₃)δ 7.50-7.26 (7 H, m), 5.60 (1 H, dd, J=4.8, 11.4Hz), 4.47-4.38 (1 H, m), 4.19 (2 H, s), 3.49 (1 H, dd, J=11.7, 12.1 Hz),3.25-3.10 (1 H, m), 2.84 (1 H, br.d, J=9.5 Hz), 2.75-2.60 (2 H, m),2.50-2.35 (2 H, m), 2.35-2.20 (2 H, m), 1.90-1.70 (1 H, m).

1R(KBr) 3450, 1640 cm⁻¹.

MS m/z: 442(M⁺).

HCl salt:amorphous solid.

Anal. Calcd for C₂₀ H₂₁ Cl₃ N₂ O₃.HCl.0.2H₂ O: C, 49.65; H, 4.67; N,5.79.

Found: C, 49.42; H, 4.39; N, 5.96.

EXAMPLE 27 N-Hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!-2-(2,4,6-trimethylphenyl)acetamide

This was prepared from2-(R)-phenyl-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethanol and2,4,6-trimethylphenylacetic acid in 67.8% yield according to a proceduresimilar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 5 7.45-7.25 (5 H, m), 6.81 (2 H, s), 5.80-5.65(1 H, m), 4.40-4.30 (1 H, m), 3.86 (2 H, s), 3.49 (1 H, dd, =11.7, 13.2z), 3.20-3.10 (1 H, m), 2.80 (1 H, br.d, J=10.3 Hz), 2.65-2.50 (2 H,m), 2.35-2.25 (3 H, m), 2.23 (3 H, s), 2.18 (6 H, s), 1.90-1.65 (1 H,m), 1.65-1.50 (1 H, m).

1R(neat): 3250, 1630 cm⁻¹.

MS m/z: 382(M⁺).

HCl salt: amorphous solid.

Anal. Calcd for C₂₃ H₃₀ N₂ O₃.HCl.0.2H₂ O: C, 64.01; H, 7.57; N, 6.49.

Found: C, 64.08; H, 7.85; N, 6.61

EXAMPLE 28 2-(2,3-Dichlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was prepared from 2-(R)-phenyl-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethanol and2,3-dichlorophenylacetic acid in 56% yield according to a proceduresimlar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃) δ 7.50-7.05 (8 H, m), 5.69 (1 H, dd, J=5.1,11.4 Hz), 5.00 -3.00 (2 H, almost flat br.s), 4.45-4.35 (1 H, m), 4.10(1 H, d, J=16.1 Hz), 3.92 (1 H, d, J=16.1 Hz), 3.48 (1 H, dd, J=11.7,12.1 Hz), 3.20-3.10 (iH, m), 2.82 (1 H, d, J=10.3 Hz), 2.70-2.55 (2 H,m), 2.45-2.20 (2 H, m), 1.80-1.70 (1 H, m).

1R(neat): 3200, 1640 cm⁻¹.

MS m/z: 408(M⁺).

HCl salt: mp 155.3-158.1° C.

Anal. Calcd for C₂₀ H₂₀ H₂₂ Cl₂ N₂ O₃.HCl: C, 53.89; H, 5.20; N, 6.28.

Found: C, 53.72; H, 5.24; N, 6.16.

EXAMPLE 29 2-(2,4-Dichlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was prepared from2-(R)-phenyl-2-(3-(S)-tetrahydroyranyloxypyrrolidin-1-yl)ethanol and2,4-dichlorophenylacetic acid in 71.9% yield according to a proceduresimilar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.45-7.15 (8 H, m), 5.69 (1H, dd, J=5.1, 11.4Hz), 6.50-4.50 (2 H, almost flat br.s), 4.35-4.25 (1 H, m), 4.00 (1 H,d, J=16.1 Hz), 3.86 (1 H, d, J=16.1 Hz), 3.47 (1 H, dd, J=11.7, 12.1Hz), 3.20-31.10 (1 H, m), 2.83 (1 H, d, J=10.6 Hz), 2.61 (2 H, dd,J=5.5, 12.1 Hz), 2.45-2.20 (2 H, m), 1.80-1.65 (1 H, m).

1R(neat): 3200, 1635 cm⁻¹.

MS m/z: 408(M⁺).

HCl salt: mp 149-151.5° C.

Anal. Calcd for C₂₀ H₂₂ Cl₂ N₂ O₃.HCl.0.2 H₂ O: C, 53.46; H, 5.25; N,6.23.

Found: C, 53.46; H, 5.19; N, 6.19.

EXAMPLE 30 2-(2,5-Dichlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was prepared from2-(R)-phenyl-2-(3-(S)-tetrahydropyranyloxypyrrolidin 1-yl)ethanol and2,5-dichlorophenylacetic acid in 56.3% yield according to a proceduresimilar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.45-7.15 (8 H, m), 5.69 (1 H, dd, J=5.1, 11.0Hz), 5.60-4.50 (2 H, almost flat br.s), 4.35-4.25 (1 H, m), 4.03 (1 H dJ=16.1 Hz), 3.86 (1 H, d, J=16.1 Hz), 3.47 (1 H, t, J=11.7 Hz),3.20-3.10 (1 H, m), 2.82 (1 H, d, J=10.6 Hz), 2.63 (2 H, dd, J=5.1, 12.1Hz), 2.45-2.20 (2 H, m), 1.85-1.70 (1 H, m). 1R(neat): 3200, 1635 cm⁻¹.

MS m/z: 408(M⁺).

HCl salt: 157.5-158.2° C.

Anal. Calcd for C₂₀ H₂₂ Cl₂ N₂ O₃.HCl.0.2H₂ O: C, 53.46; H, 5.25; N,6.23.

Found: C, 53.35; H, 5.21; N, 6.14.

PREPARATION 72-(3-(S)-Methoxymethyloxypyrrolidin-1-yl)-2-(R)-phenylethanol

To a stirred solution of (S)-(-)-butanetriol 10.61 g, 0.1 mol) inpyridine (50 ml) was added p-toluenesulfonyl chloride (38.13 g, 0.2 mol)by portions at 0° C. (ice bath). After 1 stirring, the reaction mixturewas poured into c-HCl aqueous solution including ice and acidified topH2. The mixture was extracted with ethyl acetate (100 ml×3). Theextract combined was washed with brine, dried (Na₂ SO₄), andconcentrated to give 36.22 g of i)ale brown clear oil. To a stirredsolution of this crude ditosylate (36.22 g) and methylal (50 ml) in CH₂Cl₂ (50 ml) was added P₂ O₅ (20 g). After 1 h stirring, another 10 g otP₂ O₅ was added to the reaction mixture. After 2 h stirring, the CH₂ Cl₂layer was separated. Residual dark brown solid was washed with CH₂ Cl₂.The combined CH₂ Cl₂ layer was washed with NaHCO₃ aqueous solution,dried (Na₂ SO₄), and concentrated to give 38.51 g of brown viscous oil.A mixture of this oil (38.51 g, 84 mmol), (R)-(-)-2-phenylglycinol(10.97 g, 80 mmol), and triethylamine (23 mmol, 160 mmol) in ethanol (40ml) was retluxed with stirring for 15 h. The solvent was evaporated andthe residue was dissolved in CH₂ Cl₂ (200 ml), washed with NaHCO₃aqueous solution and brine, dried (Na,SO₄), and concentrated to give28.43 g of brown viscous oil. This oil was purified by columnchromatography (silica gel 200 g, CH₂ Cl₂ /methanol: 40/1 to 20/1) toafford 9.74 g (48.4%) of clear brown viscous oil.

¹ H NMR (270 MHz, CDCl₃)δ 7.40-7.25 (5 H, m), 4.62 (1 H, d, J=7.0 Hz),4.58 (1 H, d, J=6.6 Hz), 4.26-4.18 (1 H, m), 3.92 (1 H, dd, J=6.2, 11.0Hz), 3.82 (1 H, dd, J=5.5, 11.0 Hz), 3.54 (2 H, t, J=5.9 Hz), 3.33 (3 H,s), 2.93 (1 H, br.s), 2.85-2.66 (3 H, m), 2.56-2.47 (1 H, m), 2.16-2.02(1 H, In), 1.88-1.77 (1 H, m).

EXAMPLE 31 2-(2,6-Dichlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was prepared from2-(3-(S)-methoxymethyloxypyrrolidin-1-yl)-2-(R)-phenylethanol and2,6-dichlorophenylacetic acid in 47.2% yield according to a proceduresimilar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.50-7.25 (7 H, m), 7.20-7.10 (1 H, m), 5.71(1 H, dd, J=5.1, 11.4 Hz), 5.40-3.70 (2 H, almost flat br.s), 4.50-4.40(1 H, m), 4.25 (2 H, s), 3.50 (1 H, dd, J=11.0, 12.5 Hz), 3.28-3.15 (1H, m), 2.87 (1 H, d, J=10.3 Hz), 2.75-2.55 (2 H, m), 2.50-2.25 (2 H, m),1.90-1.70 (1 H, m).

1R(KBr): 3400, 1640 cm⁻¹.

MS m/z: 408(M⁺).

HCl salt: mp 95.5-96.8° C.

Anal. Calcd for C₂₀ H₂₂ Cl₂ N₂ O₃.HCl.0.5 H₂ O: C, 52.82; H, 5.32; N,6.16.

Found: C, 52.61; H, 5.13; N, 6.10.

EXAMPLE 32 2-(3,5-Dichlorophenyl)-N-hydroxy-N-2-3-(S)-hydroxypyrrolidin-1-yl)-10(S)-phenylethyl!acetamide

This was prepared from2-(3-(S)-methoxymethyloxypyrrolidin-1-yl)-2-(R)-phenylethanol and3,5-dichlorophenylacetic acid in 47.8% yield according to a proceduresimilar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.45-7.15 (8 H, m), 5.63 (1 H, dd, J=5.5, 11.0Hz), 4.50-3.00 (2 H, almost flat br.s), 4.40-4.28 (1 H, m), 3.87 (1 H,d, J=14.3 Hz), 3.71 (1 H, d, J=14.3 Hz), 3.39 (1 H, dd, J=11.4, 12.1Hz), 3.05-2.95 1 H, m), 2.74 (1 H, d, J=11.0 Hz), 2.65 (1 H, dd, J=5.5,12.5 Hz), 2.54 (1 H, dd, J=5.5, 10.6 Hz), 2.45-2.30 (1 H, m), 2.25-2.10(1 H, m), 1.70-1.55 (1 H, m).

1R(neat): 3350, 1650 cm⁻¹.

MS m/z: 408(M⁺).

HCl salt: amorphous solid.

Anal. Calcd for C₂₀ H₂₂ Cl₂ N₂ O₃.HCl.2H₂ O: C, 49.86; H, 5.65; N, 5.81.

Found: C, 49.49; H, 5.53 N, 5.59.

EXAMPLE 33 N-Hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!-2-(2,3,6-trichlorophenyl)acetamide

This was prepared from2-(3-(S)-methoxymethyloxypyrrolidin-1-yl)-2-(R)-phenylethanol and2,3,6-trichlorophenylacetic acid in 46.7% yield according to a proceduresimilar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.45-7.20 (7 H, m), 5.69 (1 H, dd, J=4.8, 11.0Hz), 5.00-3.50 (2 H, almost flat br.s), 4.50-4.40 (1 H, m),4.29 (2 H,s), 3.49 (1 H, t, J=11.7 Hz), 3.25-3.15 (1 H, m), 2.85 (1 H, d, J=10.3Hz), 2.70-2.60 (2 H, m), 2.45-2.20 (2 H, m), 1.90-1.70 (1 H, m).

1R(KBr): 3400, 1640 cm⁻¹.

MS m/z: 442(M⁺).

HCl salt: mp 102-103° C.

Anal. Calcd for C₂₀ H₂₁ Cl₃ N₂ O₃.HCl.H₂ O: C, 48.21; H, 4.86; N, 5.62.

Found: C, 48.40; H, 4.64; N, 5.52.

EXAMPLE 34 2(Benzo b!furan-4-yl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was prepared from2-(3-(S)-methoxymethyloxypyrrolidin-1-yl)-2-(R)-phenylethanol and4-benzo b!furanacetic acid in 57.5% yield according to a proceduresimilar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.64 (1 H, d, J=2.2 Hz), 7.50-7.25 (7 H, m),7.14 (1 H, d, J=7.3 Hz), 6.84 (1 H, dd, J=0.7, 2.2 Hz), 5.61 (1 H,dd,=5.5, 11.4 Hz), 4.24 (1 H,d, J=13.6 Hz), 4.05-3.95 (1 H, m), 3.91 (1H, d, J=13.2 Hz), 3.31 (1 H, dd, J=11.7, 12.1 Hz), 2.75-2.65 (1 H, m),2.63-2.50 (2 H, m), 2.30 (1 H, dd, J=5.1, 10.3 Hz), 2.20-2.10 (1 H, m),2.00-1.85 (1 H, m).

1R(neat): 3400, 1635 cm⁻¹.

MS m/z: 380(M⁺).

HCl salt: amorphous solid.

Anal. Calcd for C₂₂ H₂₄ N₂ O₄.HCl.1.1H₂ O: C, 60.51; H, 6.28; N, 6.41

Found: C, 60.31; H, 5.98; N, 6.47.

EXAMPLE 35 N-Hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!-2-(1-tetralon-6-yl)acetamide

This was prepared from2-(3-(S)-methoxymethyloxypyrrolidin-1-yl)-2-(R)-phenylethanol and(1-tetralon-6-yl)acetic acid in 59.4% yield according to a proceduresimilar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.96 (1 H, d, J=8.1 Hz), 7.40-7 18 (7 H, m),5.66 (1 H, dd, J=5.5, 11.0 Hz), 4.30-4.20 (1 H, m), 3.94 (1 H, d, J=4.3Hz), 3.81 (1 H, d, J=13.9 Hz), 3.80-2.00 (2 H, almost flat br.s), 3.40(1 H, dd, J=11.7, 12.1 Hz), 3.00-2.85 (3 H, m), 2.80-2.50 (5 H, m),2.45-2.30 (1 H, m), 2.20-2.05 (3 H, m), 1.65-1.50 (1 H, m).

1R(neat): 3400, 1680, 1640 cm⁻¹.

MS m/z: 408(M⁺).

HCl salt: amorphous solid.

Anal. Calcd for C₂₄ H₂₈ N₂ O₄.HCl.1.2H₂,O: C, 61.78; H, 6.78; N, 6.00.

Found: C, 61.60; H, 6.59; N, 6.35.

EXAMPLE 36 2-(3,4Dimethylphenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was prepared from2-(3-(S)-methoxymethyloxypyrrolidin-1-yl)-2-(R)-phenylethanol and3,4-dimethylplenylacetic acid in 66.8% yield according to a proceduresimilar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.45-7.25 (5 H, m), 7.20-7.00 (3 H, m), 5.66(1 H, dd, J=5.1, 11.4 Hz), 4.25-4.10 (1 H, m), 3.87 (1 H, d, J=13.9 Hz),3.67 (1 H, d, J=13.9 Hz), 3.37 (1 H, dd, J=11.7, 12.1 Hz), 3.00-2.85 (1H, m), 2.71 (1 H, d, J=9.9 Hz), 2.55 (1 H, dd, J=5.5, 12.5 Hz), 2.42 (1H, dd, J=5.1, 9.9 Hz), 2.35-2.05 (9 H, m, including each 3 H, s, at 2.22and 2.21 ppm), 1.80-1.35 (2 H, m).

1R(neat): 3350, 1630 cm⁻¹.

MS m/z: 368(M⁺).

HCl salt: amorphous solid.

Anal. Calcd for C₂₂ H₂₈ N₂ O₃.HCl.1.8 H₂ O: C, 60.42; H, 7.51; N, 6.41.

Found: C, 60.51; H, 7.71; N, 6.29.

EXAMPLE 37 2-(3,4-Dichlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(R)-phenylethyl!acetamide

This was prepared from2-(3-(S)-methoxymethyloxypyrrolidon-1-yl)-2-(S)-phenylethanol and3,4-clichlorophenylacetic acid in 32.8% yield according to a proceduresimilar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.45-7.25 (7 H, m), 7.13 (1 H, dd, J=1.5, 8.1Hz), 5.61 (1 H, dd, J=5.5, 10.6 Hz), 5.00-3.90 (2 H, almost flat br.s),4.45-4.35 (1 H, m), 3.85 (1 H, d, J=14.7 Hz), 3.77 (1 H, d, J=14.3 Hz),3.37 (1 H, dd, J=11.0, 12.5 Hz), 2.89 (1 H, dd, J=4.7, 8.4 Hz), 280-2.60(3 H, m), 2.45-2.35 (1 H, m), 2.15-2.00 (1 H, m), 1.80-1.65 (11, m).

1R(KBr): 3450, 3250, 1650 cm⁻¹.

MS m/z: 408(M⁺).

mp 125.5-126.0° C.

α!_(D) =-95.4° (c=0.218, methanol)

Anal. Calcd for C₂₀ H₂₂ Cl₂ N₂ O₃ : C 58.69; H, 5.42; N, 6.84

Found: C, 58.51; H, 5.42; N, 6.70.

EXAMPLE 38 2-(3,4-Difluorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was prepared from2-(3-(S)-methoxymethyloxypyrrolidin-1-yl)-2-(R)-phenylethanol and3,4-difluorophenylacetic acid in 53.6% yield according to a proceduresimilar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.40-7.25 (5 H, m), 7.18-6.95 (3 H, m), 5.65(1 H, dd, J=5.5, 11.4 Hz), 5.00-3.90 (1H, almost flat br.s), 4.35-4.25 1H, m), 3.82 (1 H, d, J=14.3 Hz), 3.74 (1 H, d, J=14.3 Hz), 3.40 (1 H,dd, J=10.6, 13.2 Hz), 2.95 (1 H, dt, J=4.4, 8.8 Hz), 2.75 (1 H, dd,J=10.6 Hz), 2.61 (1 H, dd, J=5.1, 12.5 Hz), 2.51 (1 H, dd, J=5.5, 10.6Hz), 2.40-2.10 (2 H, m), 1.70-1.50 (1 H, m).

1R(neat): 3350, 3250, 1630 cm⁻¹.

MS m/z: 376(M⁺).

HCl salt amorphous solid.

Anal. Calcd for C₂₀ H₂₂ F₂ N₂ O₃.HCl.0.5 H₂ O: C, 56.94; H, 5.73; N,6.64.

Found: C, 57.21; H, 6.07; N, 6.63.

EXAMPLE 39 2-(Benzo b!thiophen-4-yl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was prepared from2-(3-(S)-methoxymethyloxypyrrolidin-1-yl)-2-(R)-phenylethanol and (benzob!thiophen-4-yl)acetic acid in 48.8% yield according to a proceduresimilar to that described in Preparation 4, Example 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.79 (1 H, d, J=7.7 Hz), 7.66 (1 H, d, J=5.5Hz), 7.50-7.20 (8 H, m), 5.60 (1 H, dd, J=5.5, 11.4 Hz), 4.60-3.20 (2 Halmost flat br.s), 4.32 (1 H, d, J=13.6 Hz), 4.01 (1 H, d, J=13.6 Hz),4.00-3.90 (1 H, m), 3.30 (1 H, dd, J=11.7, 12.1 Hz), 2.70-2.45 (3 H, m),2.28 (1 H, dd, J=5.1, 10.3 Hz), 2.20-2.10 (1 H, m), 1.95-1.80 (1 H, m),1.20-1.05 (1 H, m).

1R(neat): 3400, 3200, 1630 cm⁻¹.

MS m/z: 396(M⁺).

HCl salt: amorphous solid.

Anal. Calcd for C₂₂ H₂₄ N₂ O₃ S.HCl.0.5H₂ O: C, 59.79; H, 5.93; N, 6.34.

Found: C, 59.85; H, 6.09; N, 6.27.

EXAMPLE 40 N-Hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl!-1-(S)-phenylethyl-2-(3,4-methylenedioxyphenyl!acetamide

This was prepared from2-(3-(S)-methoxymethyloxypyrrolidin-1-yl)-2-(R)-phenylethanol and3,4-methylenedioxyphenylacetic acid in 59.7% yield according to aprocedure similar to that described in Preparation 4, Examples 10 and11.

¹ H NMR (270 MHz, CDCl₃)δ 7.45-7.25 (5 H, m), 6.85-6.70 3 H, m), 5.92 (2H, s), 5.66 (1 H, dd, J=5.5, 11.4 Hz), 4.50-3.30 (2 H, almost flatbr.s), 4.30-4.20 (1 H, m), 3.86(1 H, d, J=13.6 Hz),3.64 (1 H, d, J=13.9Hz), 3.39(1 H, t, J=12.1 Hz), 3.05-2.95 (1 H, m), 2.72 (1 H, d, J=10.3Hz), 2.59 (1 H, dd, J=5.5, 12.5 Hz), 2.48 (1 H, dd, J=5.5, 10.3 Hz),2.35-2.10 (2 H, m), 1.65-1.50 (1 H, m).

1R(neat) 3400, 3250, 1630 cm⁻¹.

MS m/z: 384(M⁺).

HCl salt amorphous solid.

Anal. Calcd for C₂₁ H₂₄ N₂ O₅.HCl.1.4H₂ O: C, 56.54; H, 6.28; N, 6.28.

Found: C, 56.74; H, 6.38; N, 5.89.

EXAMPLE 41 2-(3,5-Difluorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

This was prepared from2-(3-(S)-methoxymethyloxypyrrolidin-1-yl)-2-(R)-phenylethanol and3,4-difluorophenylacetic acid in 40.0% yield according to a proceduresimilar to that described in Preparation 4, Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.40-7.25 (5 H, m), 6.82 (2 H, d, J=8.1 Hz),6.72-6.64 (1 H, m), 5.65 (1 H, d(1 H, dd, J=5.1, 11.0 Hz), 5.30-4.20 (2H, almost flat br.s), 4.40-4.30 (1 H, m), 3.86 (1 H, d, J=14.3 Hz), 3.74(1 H, d, J=14.3 Hz) 3.41 (1 H, dd, J=11.7, 12.1 Hz), 3.10-2.95 (1 H, m),2.76 (1 H, d, J=10.6 Hz), 2.61 (H, dd, J=5.1, 12.5 Hz), 2.52 (1 H, dd,J=5.5, 10.6 Hz), 2.40-2.10 (2 H, m), 1.70-1.5 (1 H, m).

1R(neat): 3350, 3200, 1630 cm⁻¹.

MS m/z: 376(M⁺).

HCl salt: amorphous solid.

Anal. Calcd for C₂₀ H₂₂ F₂ N₂ O₃.HCl.0.5 H₂ O: C, 56.94; H, 5.73; N,6.64.

Found: C, 57.01; H, 5.93; N, 6.45.

PREPARATION 8 1-Benzyl-3-(R)-tetrahydropyranyloxypyrrolidine

To a stirred solution of (R)-(+)-1-benzyl-3-pyrrolidinol (5.00 g, 28mmol) and D-camphor-10-sulfonic acid (6.97 g, 30 mmol) in CH₂ Cl₂ (10ml) was added 3,4-dihydro-2H-pyran (20 ml) at rt and the reactionmixture was stirred for 14 h (in most cases, the reaction was completedafter exothermic reaction subsided). The reaction mixture was dilutedwith CH₂ Cl₂ (100 ml), washed with saturated NaHCO₃ aqueous solution,dried (Na₂ SO₄), and concentrated to give brown oil. This tas purifiedby column chromatography (silica gel:200 g, CH₂ Cl₂ /MeOH:40/1 aseluent) to give 8.78 g (97.6%) of desired compound as brown oil.

¹ H NMR (270 MHz, CDCl₃)δ 7.34-7.22 (5 H, m), 4.61 (0.5 H, dd, J=2.9,4.4 Hz), 4.54 (0.5 H, dd, J=2.9, 4.4 Hz), 4.42-4.31 (1 H, m), 3.90-3.79(1 H, m), 3.67 (1 H, d, J=12.8 Hz), 3.59 (0.5 H, d, J=12.8 Hz), 3.58(0.5 H, d, J=12.8 Hz), 3.50-3.40 (1 H, m), 2.88 (0.5 H, dd, J=6.6, 10.3Hz), 2.74-2.45 (3.5 H, m), 2.25-2.05 (1 H, m), 1.95-1.45 (7 H, m).

PREPARATION 9 3-(R)-Tetrahydropyranyloxypyrrolidine

A mixture of 1-benzyl-3-(R)-tetrahydropyranyloxypyrolidine(8.78 g, 27.3mmol) and Pearlman's catalyst (3.50 g) in MeOH (100 ml) was stirredunder hydrogen atmosphere at rt for 4 h. After removal of the catalystby Celite filtration, the filtrate was concentrated to give 5.74 g ofclear light brown oil. This was used for the next reaction withoutpurification.

¹ H NMR (270 MHz, CDCl₃)δ 4.62 (1 H, br.s), 4.45-4.30 (1 H, m),3.90-3.80 (1 H, m), 3.55-3.45 (1 H, m), 3.20-2.80 (5 H, m), 2.00-1.40 (8H, m).

PREPARATION 101-(S)-Phenyl-2-(3-(R)-tetrahydropyranyloxypyrrolidin-1-yl)ethanol and2-(R)-Phenyl-2-(3-(R)-tetrahydropyranyloxypyrrolidin-1-yl)ethanol

A mixture of 3-(R)-tetrahydropyranyloxypyrrolidine (1.43 g, 8.32 mmol)and (S)-(-)-styrene oxide (1.00 g, 8.32 mmol) in EtOH (10 ml) wasrefluxed with stirring for 1 h. Evaporation of the solvent gave 3.098 gof brown oil, which was purified by column chromatography(silica gel:100 g, CH₂ Cl₂ MeOH:40/1 to 15/1 as eluent) to afford 1.68 g (69.3%) ofclear light brown oil as about to 1 mixture of title compounds in which1-(S)-phenyl-2-(3-(R)-tetrahydro-pyranylqxypyrrolidin-1-yl)ethanol wasmain.

¹ H NMR (270 MHz, CDCl₃)δ 7.40-7.24 (5 H, m), 4.72 and 4.68 (total 0.67H, app.each d, J=2.6 Hz, OCHO), 4.63-4.55 (1 H,m, PhCHOH and OCHO),4.43-4.25 (1 H, m, OCHCH₂ N), 3.89-3.81 (1.67 H, m), 3.52-3.46 (1.33 H,m), 2.88-2.47 (5.33 H, m), 2.15-1.90 (2 H, m), 1.86-1.66 (3 H, m),1.58-1.51 (4 H, m).

EXAMPLE 42 2-(3.4-Dichlorophenyl)-N-1-(S)-phenyl-2-(3-(R)-tetrahydropyranyloxypyrrolidin-1-yl)ethyl!-N-tetrahydropyranyloxyacetamide

To a stirred solution of1-(S)-phenyl-2-(3-(R)-tetralydropyranyloxypyrrolidin-1-yl)ethanol (1.67g, 5.73 mmol) and Et₃ N (0.96 ml, 6.88 mmol) in CH₂ Cl₂ (20 ml) wasadded dropwise mesyl chloride (0.53 ml, 6.88 mmol) at 0° C. The reactionmixture was stirred at rt for 16 h. The reaction mixture was washed withsaturated NaHCO₃ aqueous solution and brine, dried (Na₂ SO₄), andconcentrated to give 2.02 g of brown oil. This oil was tised for nextreaction without purification.

¹ H NMR (270 MHz, CDCl₃)δ 7.42-7.30 (5 H, m), 4.94 (1 H, dd, J=5.9, 8.1Hz, PhCHCl), 4.60 and 4.52 (total 1 H, each m, OCHO), 4.35-4.31 (1 H, m,OCHCH₂ N), 3.88-3.82 (1 H, m), 3.48-3.45 (1 H, m), 3.25-3.17 (1 H, m),3.0-2.69 (3 H, m), 2.66-2.50 (3 H, m), 1.88-1.67 (3 H, m), 1.56-1.51 (4H, m).

A mixture of crude chloride derivative (2.02 g, 5.7 mmol) andO-(tetra-hydropyranyl)hydroxylamine (0.806 g, 6.88 mmol) in EtOH (1 ml)was refluxed with stirring for 0.5 h. The reaction mixture wasconcentrated, diluted with CH₂ Cl₂ (30 ml), washed with saturated NaHCO₃aqueous solution and brine, dried (Na₂ SO₄), and concentrated to give2.59 g of brown oil. This oil was usedl for the next reaction withoutpurification.

A mixture of the above crude amine derivative (2.59 g, 5.73 mmol),3,4-dichlorophenylacetic acid (1.4 1 g, 6.88 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrocloride (abbreviatedas WSC, 1.32 g, 6.88 mmol) in CH₂ Cl₂ (15 ml) was stirred at rt for 0.5h. The reaction mixture was washed with saturated NaHCO₃ aqueoussolution and brine, dried (Na₂ SO₄), and concentrated to give 4.12 g ofbrown oil. This oil was purified by column chromatography (silica gel:100 g, CH₂ Cl₂ /MeOH:50/1 to 40/1 as eluent) to give 2.22 g(67.1%) ofpale yellow oil.

EXAMPLE 43 2-(3,4-Dichlorophenyl)-N-hydroxy-N-2-(3(R)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide

A mixture of above amide derivative (2.20 g, 3.81 mmol) and HCl gascontaining MeOH (10 ml) was stirred at rt for 1 h. The reaction mixturewas concentrated, basifiecl with NH₃ aqueous solution, and extractedwith CH₂ Cl₂ (30 ml). The extract was washed with brine, dried (Na₂SO₄), and concentrated to give light brown powder. This was collected byfiltration and washed with hexane to afford 1.117 g (71.6%) of lightbrown powder.

¹ H NMR (270 MHz, CDCl₃)δ 7.41-7.28 (7 H, m), 7.13 (1 H, dd J=1.8, 8.4Hz), 5.61 (1 H, dd, J=5.5, 10.6 Hz), 4.50-3.50 (2 H, almost flat br.s),4.10-4.35 (1 H, m), 3.84 (1 H, d, J=14.7 Hz), 3.77 (1 H, d, J=14.3 Hz),3.38 (1 H, dd, J=11.0, 12.1 Hz), 2.94-2.85 (1 H, m), 2.74-2.63 (3 H, m),2.44-2.35 (1 H, m), 2.15-2.611 (1 H, m), 1.80-1.65 (1 H, m), 1R(KBr):3250, 1650 cm⁻¹.

MS m/z: 408(M⁺)

HCl salt: amorphous solid.

Anal. Calccl for C₂₀,H₂₂ Cl₂ N₂ OHC.0.8H₂ O: C,52.20; H, 5.39; N, 6.09.Found: C, 52.22; H, 5.39; N, 6.12.

EXAMPLE 44 2-(3,4-Dichlorophenyl)-N-hydroxy-N-2-(3-(R)hydroxypyrrolidin-1-yl)-1-(R)-phenylethyl!acetamide

This was prepared from 3-(R)-tetrahydropyranyloxypyrrolidine and(R)-(+)-styrene oxide in 33.3% yield according to the procedure similarto that described in Examples 3 to 5.

¹ H NMR (270 MHz, CDCl₃)δ 7.38 (1 H, dd, J=8.4 Hz), 7.36-7.27 (6 H, m),7.13 (1 H, dd, J=1.8, 8.1 Hz), 5.64 (1 H, dd, J=5.1, 11.0 Hz), 5.00-3.50(2 H, almost flat br.s), 4.35-4.25 (1 H, m), 3.84 (1 H, d, J=14.3 Hz),3.73 (1 H, d, J=13.2 Hz), 3.40 (1 H, dd, J=11.4, 12.5 Hz), 3.05-2.95 (1H, m), 2.74 (1 H, br.d, J=10.3 Hz), 2.62 (1 H, dd, J=5.1, 12.5 Hz), 2.51(1 H, dd, J=5.5, 10.6 Hz), 2.40-2.25 (1 H m), 2.25-2.10 (1 H, m),1.70-1.55 (1 H, m).

1R(KBr) 3400, 3200, 1640 cm⁻¹.

MS m/z: 408(M⁺)

HCl salt: amorphous solid

Anal. Calcd for C₂₀ H₂₂ Cl₂ N₂ O₃.HCl.0.5H₂ O: C, 52.82; H, 5.32; N,6.16.

Found: C, 52.71; H, 5.59; N, 6.15.

PREPARATION 11 (S)1-(3-Methylphenyl)-1,2-ethanediol

A mixture of 3-methylstyrene (1.69 ml, 12.7 mmol), and AD-mix-60 (17.78g, 12.7 mmol) in water (65 ml) and t-BuOH (65 ml) was stirred at 0° C.for 3.5 h. To this reaction mixture was added Na₂ SO₁ (20 g) and themixture was stirred at rt for 1 h. The reaction mixture was extracteclwith ethyl acetate. The extract was washed with brine, dried (Na₂ SO₄),and concentrated to give 2.07 g of light brown oil, which was purifiedby column chromatography (silica gel: 110 g, ethyl acetate/hexane:3/2)to afford 1.89 g(98%) of desired product as light brown oil.

¹ H NMR (270 MHz, CDCl₃)δ 7.24 (1 H, dd, J=7.3, 7.7 Hz), 7.19-7.09 (3 H,m), 4.77 (1 H, dd, J=3.7, 8.1 Hz), 3.74 (1 H, dd, J=3.7, 11.4 Hz), 3.65(1 H, dd, J=8.1, 11.4 Hz), 2.82 (1 H, br.s), 2.35 (3 H, s), 1.77 (1 H,br.s).

PREPARATION 12 (S)-1-(3-Methylphenyl)-1,2-ethanediol 2-tosylate

To a stirred solutioll of (S)-1-(3-methylphenyl)-1,2-ethanediol (1.78 g,11.7 mmol) in pyridine (35 ml) was added p-toluenesulfonyl chloride(2.46 g, 12.9 mmol), and 4-dimethylaminopyridine (1.58 g, 12.9mmol) at0° C. and the reaction mixture was stirred at 0° C. to rt for 17 h. Thereaction mixture was acidified with 6 N HCl aqueous solution andextracted with CH₂ Cl₂. The extract was washed with water and brine,dried (Na₂ SO₄), and concentrated to give 3.02 g of yellow oil, whichwas purified by column chromatography (silica gel: 100 g, ethylacetatelhexane:1/9 to 1/3) to afford 2.63 g (73%) of desired product aslight yellow oil. Its optical purity was 97% ee by HPLC employing achiral stationary phase (chiral pak AS, Daicel Chemical Industries,eluted with n-hexane/EtOH:98/2; detection time:: 55 min for (R)-isomer59 min for (S)-isomer).

¹ H NMR (270 MHz, CDCl₃)δ 7.77 (2 H, d, J=8.4 Hz), 7.33 (2 H, d, J=8.1Hz), 7.22 (1 H, dd, J=7.7, 8.1 Hz), 7.15-7.05 (3 H, m), 4.94 (1 H, ddd,J=2.9, 2.9, 8.4 Hz), 4.15 (1 H, dd, J=2.9, 10.3 Hz), 4.04 (1 H, dd,J=8.4, 10.3 Hz), 2.54 (1 H, br.d, J=2.9 Hz), 2.45 (3 H, s), 2.33 (3 H,s), 1.58 (3 H, s).

PREPARATION 132-(3-(S)-Methoxymethyloxypyrrolidin-1-yl)(S)-(3-methylphenyl)-ethanoland2(3-(S)-methoxymethyloxypyrrolidin-1-yl)-2-(R)-(3-methylphenyl)ethanol

A mixture of (S)-1-(3-methylphenyl)-1,2-ethanediol 2-tosylate (2.63 g,8.59 mmol), (5)-3-methoxymethyloxypyrrolidine (1.24 g, 9,45 mmol), andK₂ CO₃ (1.31 g, 9.45 mmol) in ethanol (25 ml) was refluxed with stirringfor 2 h. After removal of the solvent by evaporation, the residue wasdiluted with water and extracted with CH₂ Cl₂. The extract was washedwith brine, dried (Na₂ SO₄), and concentrated to give 2.11 g of brownoil, which was purified by column chromatography (silica gel:110 g, CH₂Cl₂ /MeOH: 15/1 to 10/1) to afford 1.72 g (76%) of 3 to 2 mixture ofdesired products as a light brown oil.

¹ H NMR (270 MHz, CDCl₃)δ 7.26-7.05 (4 H, m), 4.68 (0.6 H, dd, J=2.9,10.6 Hz, PhCHOH), 4.67 (0.6 H, d, J=7.0 Hz OCH₂ O), 4.63 (0.6 H, d,J=6.6 Hz, OCH₂ O), 4.62 (0.4 H, d, J=7.0 Hz, OCH₂ O), 4.59 (0.4 H, d,J=7.0 Hz, OCH₂ O), 4.34-4.24 (0.6 H, m, OCHCH₂ N), 4.24-4.16 (0.4 H, m,OCHCH,N ), 3.88 (0.4 H, dd, J=6.2, 10.6 Hz, CHCH₂ OH), 3.79 (0.4 H, dd,J=5.8, 11.0 Hz, CHCH₂ OH), 3.47 (0.4 H, dd, J=5.8, 6.2 Hz, NCHPh), 3.38(1.8 H, s), 3.33 (1.2 H, s), 3.0-2.92 (1.2 H, m), 2.82-2.40 (4 H, m),2.35 (3 H, s), 2.25-1.50 (3 H, m).

EXAMPLE 45 2-(3,4-Dichlorophenyl)-N-2-(3-(S)-methoxymethyloxypyrrolidin-1-(S)-(3-methylphenyl)ethyl!-N-tetrahydropyranyloxyacetamide

This was prepared from a mixture of2-(3-(S)-methoxymethyloxypyrrolidin-1-yl)-1-(S)-(3-methylphenyl)ethanoland2-(3-(S)-methoxymethyloxypyrrolidin-1-yl)-2-(R)-(3-methylphenyl)ethanolin 60% yield according to the procedure similar to that described inExample 4.

¹ H NMR (270 MHz. CDCl₃)δ 7.39 (0.5 H, d, J=1.8 Hz), 7.05 (0.5 H, d,J=8.4 Hz), 7.27-7.02 (5.5 H, m), 6.96 (0.5 H, dd, J=1.8, 8.4 Hz), 5.65(0.5 H, dd, J=5.1, 11.4 Hz, PhCHN), 5.52 (0.5 H, dd, J=4.8, 11.0 Hz,PhCHN), 5.30-5.20 (1 H, m, NOCHO), 4.64 (0.5 H, d, J=6.6 Hz, OCH₂ O),4.63 (0.5 H, d, J=7.0 Hz, OCH₂ O), 4.61 (0.5 H, d, J=6.6 Hz, OCH₂ O),4.60 (0.5 H, d, J=6.6 Hz, OCH₂ O), 4.30-4.20 (0.5 H, m, OCHCH₂ N),4.20-4.10 (0.5 H, m, OCHCH₂ N), 4.06-3.85 (3 H, m), 3.56-3.36 (1.5 H,m), 3.35 (1.5 H, s, OMe), 3.34 (1.5 H, s, OMe), 3.24-3.10 (0.5 H, m),3.01-2.80 (2 H, m), 2.66-2.40 (3 H, m), 2.34 (1.5 H, s), 2.28 (1.5 H,s), 2.15-1.15 (8 H, m).

EXAMPLE 46 2-(3,4-Dichlorophenyl)-N-hydroxy-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-(3-methylphenyl)ethyl!acetamide

This was prepared From 2-(3,4-dichlorophenyl)-N-2-(3-(S)-methoxymethyloxy-pyrrolidin-1-yl)-1-(S)-(3-methylphenyl)ethyl!-N-tetralydropyrayloxyacetamidein77%yield according to the procedure similar to that described in Example 5

¹ H NMR (270 MHz, CDCl₃)δ 7.42-7.05 (7 H, m), 5.59 (1 H, dd, J=5.1, 11.0Hz, PhCHN), 4.35-4.25 (1 H, m, CHOH), 3.85 (1 H, d, J=14.3 Hz, COCH₂Ph), 3.74 (1 H, d, J=15.8 Hz, COCH₂ Ph), 3.50-2.50 (2 H, almost flatbr.s, OHx2), 3.38 (1 H, dd, J=11.7, 12.1 Hz), 3.00-2.90 (1 H, m), 2.73(1 H, br.d, J=10.6 Hz), 2.62 (1 H, dd, J=5.1, 12.5 Hz), 2.53 (1 H, dd,J=5.5, 10.6 Hz), 2.40-2.25 (4 H, m, including 3 H, s at 2.30 ppm),2.23-2.07 (1 H, m), 1.65-1.55 (1 H, m).

1R(neat): 3350, 1650 cm⁻¹.

MS m/z: 422(M⁺)

HCl salt: amorphous solid

Anal. Calcd for C₂₁ H₂₄ Cl₂ N₂ O₃.HCl.1.5 H₂ O: C, 51.81; H, 5.80; N,5.75.

Found: C, 51.85; H, 5.72; N, 5.47.

EXAMPLE 47 N-1-(S)-(4-Chlorophenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)ethyl!-2-(3,4-dichlorophenyl)-N-hydroxyacetamide

This was prepared from 4-chlorostyrene and3-(S)-methoxymethyloxypyrrolidine in 12% overall yield according to aprocedure similar to that described in Examples 7 to 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.40 (1 H, d, J=2.2 Hz), 7.36 (1 H, d, J=8.4Hz), 7.30-7.20 (4 H, m), 7.14 (1 H, dd, J=2.2, 8.1 Hz), 5.58 (1 H, dd,J=5.1, 11.0 Hz, PhCHN), 5.00-3.00 (2 H, almost flat br.s, OHx2),4.35-4.25 (1 H, m, CHOH), 3.85 (1 H, d, J=14.3 Hz, COCH₂ Ph), 3.72 (1 H,d, J=13.9 Hz, COCH₂ Ph), 3.33 (1 H, t, J=11.7 Hz), 3.00-2.85 (1 H, m),2.74 (1 H , br.d, J=10.3 Hz), 2.65 (1 H, dd, J=5.1, 12.5 Hz), 2.60-2.45(1 H, m), 2.45-2.25 (1 H, m), 2.25-2.05 (1 H, m), 1.70-1.50 (1 H, m).

HCl salt: amorphous solid

1R(KBr): 3400, 3100, 1650 cm⁻¹.

MS m/z: 443(M+H).

Anal. Calccl for C₂₀ H₂₁ Cl₃ N₂ O₃.HCl.0.7H₂ O: C, 48.74; H, 4.79; N,5.68.

Found: C, 49.15; H, 5.2 1; N, 5.58.

EXAMPLE 48 2-(3,4-Dichlorophenyl)-N-hydroxy-N-2,3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-4-methoxyphenyl)ethyl!acetamideand 2-(3,4-dichlorophenyl)-N-hydroxy-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(R)-(4-methoxyphenyl)-ethyl!acetamide

This was prepared from 4methoxystyrene and3-(S)-methoxymethyloxypyrrolidine in 5.2% overall yield according to aprocedure similar to that described in Examples 7 to 11.

In this case racemization occurred at 1-position to afford the titlecompunds during the following reacitons (mesylation, addition ofTHPONH₂, and acylation).

¹ H NMR (270 MHz, CDCl₃)δ 7.40-7.26 (4 H, m), 7.12 (0.5 H, dd, J=2.2,8.4 Hz), 7.11 (0.5 H, dd, J=2.6, 8.4 Hz), 6.84(2 H, d, J=8.4 Hz),5.70-5.60 (1 H, m, PHCHN), 4.50-4.40 (0.5 H, m, CHOH), 4.50-3.00 (2 H,almost flat br.s, OHx2), 4.40-4.30 (0.5 H, m, CHOH), 3.84 (1 H, d,J=14.3 Hz, COCH₂ Ph), 3.79) (3 H, s), 3.73 (1 H, d, J=14.7 Hz, COCH₂Ph), 3.65-3.40 (1 H, m), 3.15-3.00 (1 H, m), 2.90-2.40 (4 H, m),2.30-2.10 (1 H, m), 1.90-1.78 (0.5 H, m), 1.78-1.60 (0.5 H, m).

HCl salt: amorphous solid

1R(KBr): 3400, 3150, 1650 cm⁻¹.

MS m/z: 438(M⁺)

Anal. Calcd for C₂₁ H₂₄ Cl₂ N₂ O₄.HCl.2.5H₂ O: C, 48.43; H, 5.81; N,5.38.

Found: C, 48.21; H, 5.75; N, 5.35.

EXAMPLE 49 2-(3,4-Dichlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-(4-trifluoromethylphenyl)ethyl!acetamide

This was prepared fom 4-trifluoromethylstyrene and3-(S)-methoxymethyloxy-pyrrolidine in 25.3% overall yield according to aprocedure similar to that described in Examples 7 to 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.60-7.35 (6 H, m), 7.20-7.10 (1 H, m), 5.65(1 H, dd, J=5.5, 11.0 Hz, PhCHN), 4.40-4.30 (1 H, m, CHOH), 3.90 (1 H,d, J=13.9 Hz, COCH₂ Ph), 3.73 (1 H, d, J=12.5 Hz, COCH₂ Ph), 3.34 (1 H,d, J=11.0, 12.5 Hz), 3.00-2.90(1 H, m), 2.75-2.65(2 H, m), 2.54(1 H, dd,J=5.1, 10.6 Hz), 2.50-2.00(4 H, m), 1.70-1.55 (1 H, m).

1R(neat): 3400, 3250, 1635 cm⁻¹.

MS m/z: 476(M⁺)

HCl salt: amorphous solid

Anal. Calcd for C₂₁ H₂₁ Cl₂ F₃ N₂ O₃.HCl.2H₂ O: C, 45.88; H, 4.77; N,5.10.

Found: C, 45.90; H, 4.83; N, 4.71.

PREPARATION 14 (S)-1-(4-Methylphenyl)-1,2-ethanediol 2-tosylate

This was prepared from 4-methylstyrene in 75% overall yield according toa procedure similar to that described in Examples 7 and 8. Opticalpurity was 98.3% ee by HPLC analysis.

¹ H NMR (270 MHz, CDCl₃) δ 7.77 (H d, J=8.1 Hz), 7.33 (2 H, d, J=8.4Hz), 7.20 (2 H, d, J=8.1 Hz), 7.14(2 H, d, J=8.1 Hz), 5.00-4.90 (1 H,m), 4.13 (1 H, dd, J=3.3, 10.3 Hz), 4.03 (1 H, d, J=8.4, 10.3 Hz), 2.49(1 H, d, J=2.9 Hz), 2.45 (3 H, s), 1.57 (3 H, s).

PREPARATION 15 (S)-4-Methylstyrene oxide

A mixture of(S)-1-(4-methylphenyl)-1,2-ethanediol2-tosylate(4.13 g, 13.5mmol) and 50% NaOH aqueous solution (5 ml) in THF (25 ml) was stirred atrt for 1 h and at 50° C. for 2 h. After cooling down to rt, the reactionmixture was diluted with water and extracted with ethyl acetate. Theextract was washed with water and brine, dried(Na₂ SO₄), andconcentrated to give 1.59 g(88%) of desired compound as pale brown oil.This oil was used for next reaction without purification.

¹ H NMR (270 MHz, CDCl₃)δ 7.20-7.10 (4 H, m), 3.83 (1 H, d, J=2.6, 4.0Hz), 3.13 (1 H, dd, J=4.0, 5.5 Hz), 2.80 (1 H, dd, J=2.6,5.5 Hz), 2.34H, s).

PREPARATION 162-(3-(S)-Methoxymethyloxypyrrolidin-1-yl)-1-(S)-(4-methylphenyl-ethanoland2-(3-(S)-methoxymethyloxypyrrolidin-1-yl)-2-(R)-(4-methylphenyl)ethanol

A mixture of (S)-4-methylstyrene oxide (1.59 g, 1.9 mmol) and3-(S)-methoxymethyloxypyrrolidine (1.55 g, 11.9 mmol) in isopropanol (25ml) was refluxed 5 for 7 h. The solvent was evaporated and the residuewas purified by column chromatography(silica gel: 150 g, CH₂ Cl₂ /MeOH:50/1 to 15/1 ) to give 2.39 g (76%) of desired products as a pale brownoil. This was 3 to 2 mixture of title compounds.

¹ H NMR (270 MHz, CDCl₃)δ 7.26 (1.2 H, d, J=8.1 Hz), 7.21-7.10 (2.8 H,m), 4.75-4.55 (2.6 H, m, including 0.6 H, d, J=6.6 Hz at 4.66 ppm, 0.6H, d, J=7.0 Hz at 4.63 ppm, 0.4 H, d, J=7.0 Hz at 4.62 ppm, 0.4 H, d,J=7.0 Hz at 4.58 ppm), 4.35-4.23 (0.6 H, m, OCHCH₂ N), 4.23-4.15 (0.4 H,m, OCHCH₂ N), 3.87 (0.4 H, dd, J=6.2, 10.6 Hz, CHCH₂ OH), 3.77 (0.4 H,dd, J=5.9, 10.6 Hz, CHCH₂ OH), 3.49 (0.4 H, dd, J=5.9, 6.2 Hz, NCHPh),3.38 (1.8 H, s), 3.33 (1.2 H, s), 3.05-2.90 (1.2 H, m), 2.80-2.40 (5 H,m), 2.34 (3 H, s), 2.25-2.00 (1 H, m), 1.95-1.75 (1 H, m).

EXAMPLE 50 2-(3,4-Dichlorophenyl)-N-hydroxy-N-2-1-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-(4-methylphenyl)ethyl!acetamide

This was prepared from2-(3-(S)-methoxymethyloxypyrrolidin-1-yl)-1-(S)-(4-methylphenyl)etianoland2-(3-(S)-methoxymethyloxypyrrolidin-1-yl)-2-(R)-(4-methylphenyl)ethanolin 29.5% overall yield according to a procedure similar to thatdescribed in Examples 10 and 11.

¹ H NMR (270 MHz, CDCl₃)δ 7.40-7.30 (2 H, m), 7.23 (2 H, app.d, J=8.1Hz), 7.11 (3 H, app.d, J=7.7 Hz), 5.64 (1 H, dd, J=5.1, 11.4 Hz, PhCHN),5.00-3.00 (2 H, almost flat br.s, OHx2), 4.40-4.30 (1 H, m, CHOH), 3.84(1 H, d, J=14.7 Hz, COCH₂ Ph), 3.73 (1 H, d, J=14.3 Hz, COCH₂ Ph), 3.46(1 H, dd, J=11.4, 12.1 Hz), 3.10-2.95 (1 H, m), 2.83 (1 H, br.d, J=11.0Hz), 2.75-2.40 (3 H, m), 2.32 (3 H, s), 2.25-2.10 (1 H, m), 1.75-1.60 (1H, m).

HCl salt: amoorpiolis solid

MS m/z: 422(M⁺)

1R(KBr): 3420, 3180, 1650 cm³¹ 1. Anal. Calcd for C₂₁ H₂₄ Cl₂ N₂O₃.HCl.0.5 H₂ O: C, 53.80; H, 5.59; N, 5.98.

Found: C, 53.51; H, 5.67; N, 6.04.

PREPARATION 17 (S)-1-(3-Methoxymethyloxyphenyl)-1,2-ethanediol

This was prepared from 3-methoxymethyloxystyrene (prepared bymethoxymethylation of 3-hydroxystyrene in a standard manner) inquantitative yield according to a procedure similar to that described inExample 7.

¹ H NMR (270 MHz, CDCl₃)δ 7.25 (1 H, dd, J=7.7, 8.1 Hz), 1.03 (1 H, d,J=1.8 Hz), 6.98-6.92 (2 H, m) 5.15 (2 H, s, OCH₂ OMe), 4.74 (1 H, dd,J=3.3, 8.1 Hz, ArCHOH), 3.71 (1 H, br.d, J=9.9 Hz, CHCH₂ OH), 3.65-3.55(2 H, m, including 1 H, dd, J=8.1, 11.0 Hz at 3.61 ppm, CHCH₂ OH), 3.44(3 H, s, OCH₂ OMe), 3.14 (1 H, br.s, OH).

PREPARATION 18 (S)-1-(3-Methoxymethyloxyphenyl)-1,2-ethanediol2-tosylate

This was prepared from (S)-1-(3-methoxymethyloxyphenyl)-1,2-ethanediolin 64% yield according to a procedure similar to that described inExample 8. Its optical purity was 96% ee by HPLC.

¹ H NMR (270 MHz, CDCl₃)δ 7.77 (2 H, d, J=8.4 Hz), 7.34 (2 H, d, J=8.1Hz), 7.25 (1 H, dd, J=7.7, 8.4 Hz), 7.00-6.92 (3 H, m), 5.15 (2 H, s),4.95 (1 H, ddd, J=3.3, 3.3, 8.4 Hz, ArCHOH), 4.15 (1 H, dd, J=3.3, 10.3Hz, CHCH₂ OTs), 4.03 (1 H, dd, J=8.4, 10.3 Hz, CHCH₂ OTs), 3.46 (3 H, s,OCH₂ OMe), 2.65 (1 H, d, J=3.3 Hz, ArCHOH), 2.45 (3 H, s, PhMe).

EXAMPLE 51 2-(3,4-Dichlorophenyl)-N-1-(S)-(3-methoxymethyloxyphenyl)-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethyl!-N-tetrahydropyranyloxy-acetamide

This was prepared from (S)-1-(3-methoxymethyloxyphenyl)-1,2-ethanediol2-tosylate in 52% overall yield according to the proceclure similar tothat described in Examples 9 and 10.

¹ H NMR (270 MHz, CDCl₃)δ 7.42-6.91 (7 H, m), 5.65 (0.5 H, dd, J=3.3,9.9 Hz, PhCHN), 5.54 (0.5 H, d, J=4.4, 11.0 Hz, PhCHN), 5.35-5.25 (1 H,m, NOCHO), 5.19 (0.5 H, d, J=6.6 Hz, OCH₂ O), 5.15 (0.5 H, d, J=6.6 Hz,OCH₂ O), 5.14 (0.5 H, d, J=7.0 Hz, OCH₂ O), 5.10 (0.5 H, d, J=7.0 Hz,OCH₂ O), 4.65-4.55 (1 H, m, CHOCHO), 4.40-4.30 (0.5 H, m, OCHCH₂ N),4.30-4.20 (0.5 H, m, OCHCH₂ N), 4.10-3.85 (4 H, m, including 0.5 H, d,J=16.5 Hz at 4.06 ppm, 5 H, d, J=16.5 Hz at 3.92 ppm, and 1 H, s at3.92ppm, COCH₂ Ph ), 3.68-3.15 (6 H, m, including each 1.5 H, s, at 3.47and 3.46 ppm, OMe), 3.02-2.80 (2 H, m), 2.66-2.35 (3 H, m), 2.20-1.15(14 H, m).

EXAMPLE 52 2-(3,4-Dichlorophenyl)-N-hydroxy-N-1-(S)-(3-hydroxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)ethyl!acetamide

This was prepared from 2-(3,4-dichlorophenyl)-N-1-(S)-(3-methoxymethyloxyphenyl)-2-(3-(S)-tetrahydropyranyloxypyrrolidin-1-yl)ethyl!-N-tetrahydropyranyloxyacetamidein 46% yield according to the procedure similar to that described inExample 11.

¹ H NMR (270 MHz, CDCl₃ and DMSOCd₆)δ 7.56 (1 H, s, PhOH), 7.40 (1 H, d,J=1.8 Hz), 7.37 (1 H, d, J=8.4 Hz), 7.17 (1 H, dd, J=1.8, 8.1 Hz), 7.11(1 H, dd, J=7.7, 8.1 Hz), 6.90-6.70 (3 H, m), 5.56 (1 H, dd, J=5.1, 10.6Hz, PhCHN), 4.30-4.20 (1 H, m, CHOH), 3.90 (1 H, dd, J=15.0 Hz, COCH₂Ph), 3.74 (1 H, d, J=14.5 Hz, COCH₂ Ph), 4.50-2.50 (2 H, almost flatbr.s, OHx2), 3.32 (1 H, dd, J=11.4, 11.7 Hz), 3.00-2.85 (1 H, m),2.75-2.55 (3 H, m, including 1 H, dd, J=5.1, 11.0 Hz), 2.40-2.30 (1 H,m), 2.15-2.00 (1 H, m), 1.80-1.60 (1 H, m).

1R(KBr): 3350, 3200, 1630 cm⁻¹ .

MS m/z: 424(M⁺)

Free amine: mp 151.6-153.1° C.

Anal. Calcd for C₂₀ H₂₂ Cl₂ N₂ O₄ 0.7H₂ O: C,54.85; H, 5.39; N, 6.40.

Found: C, 54.70;

H, 4.99; N, 6.42.

The chemical structures of the compounds prepared in the Examples 1 to52 are summarized in the following tables.

                  TABLE    ______________________________________    1 #STR7##    Ex.    #   A          Ar         R       X    ______________________________________     1  hydrogen   (S)-phenyl benzyl  3,4-dichlorophenyl     2  hydrogen   (S)-phenyl hydrogen                                      3,4-dichlorophenyl     3  hydrogen   (S)-phenyl methyl  3,4-dichlorophenyl     4  hydrogen   (S)-phenyl hydrogen                                      2,3,6-trichlorophenyl     5  hydrogen   (S)-phenyl hydrogen                                      4-trifluoro                                      methylphenyl     6  hydrogen   (S)-phenyl hydrogen                                      1-naphthyl     7  hydrogen   (S)-phenyl hydrogen                                      2,4,6-trimethyl-                                      phenyl     8  hydrogen   (S)-phenyl hydrogen                                      4-pyridyl     9  hydrogen   (S)-phenyl hydrogen                                      benzo b!furan-4-yl    10  (S)-tetra- (S)-phenyl tetrahydro-                                      3,4-dichlorophenyl        hydro-                pyranyloxy        pyranyloxy    11  (S)-hydroxy                   (S)-phenyl hydrogen                                      3,4-dichlorophenyl    12  (S)-hydroxy                   (S)-4-fluoro-                              hydrogen                                      3,4-dichlorophenyl                   phenyl    13  (S)-hydroxy                   (S)-phenyl hydrogen                                      4-bromophenyl    14  (S)-hydroxy                   (S)-phenyl hydrogen                                      3-bromophenyl    15  (S)-hydroxy                   (S)-phenyl hydrogen                                      4-fluorophenyl    16  (S)-hydroxy                   (S)-phenyl hydrogen                                      3,4-dimethoxy-                                      phenyl    17  (S)-hydroxy                   (S)-phenyl hydrogen                                      3-trifluoro-                                      methylphenyl    18  (S)-hydroxy                   (S)-phenyl hydrogen                                      4-trifluoro-                                      methylphenyl    19  (S)-hydroxy                   (S)-phenyl hydrogen                                      4-biphenyl    20  (S)-hydroxy                   (S)-phenyl hydrogen                                      4-nitrolphenyl    21  (S)-hydroxy                   (S)-phenyl hydrogen                                      3-nitrolphenyl    22  (S)-hydroxy                   (S)-phenyl hydrogen                                      4-chlorophenyl    23  (S)-hydroxy                   (S)-phenyl hydrogen                                      3-chlorophenyl    24  (S)-hydroxy                   (S)-phenyl hydrogen                                      2-chlorophenyl    25  (S)-hydroxy                   (S)-phenyl hydrogen                                      2,3,5-trichloro-                                      phenyl    26  (S)-hydroxy                   (S)-phenyl hydrogen                                      2,4,6-trichloro-                                      phenyl    27  (S)-hydroxy                   (S)-phenyl hydrogen                                      2,4,6-trimethyl-                                      phenyl    28  (S)-hydroxy                   (S)-phenyl hydrogen                                      2,3-dichlorophenyl    29  (S)-hydroxy                   (S)-phenyl hydrogen                                      2,4-dichlorophenyl    30  (S)-hydroxy                   (S)-phenyl hydrogen                                      2,5-dichlorophenyl    31  (S)-hydroxy                   (S)-phenyl hydrogen                                      2,6-dichlorophenyl    32  (S)-hydroxy                   (S)-phenyl hydrogen                                      3,5-dichlorophenyl    33  (S)-hydroxy                   (S)-phenyl hydrogen                                      2,3,6-trichloro-                                      phenyl    34  (S)-hydroxy                   (S)-phenyl hydrogen                                      benzo b!furan-4-yl    35  (S)-hydroxy                   (S)-phenyl hydrogen                                      1-tetralon-6-yl    36  (S)-hydroxy                   (S)-phenyl hydrogen                                      3,4-dimethyl-                                      phenyl    37  (S)-hydroxy                   (S)-phenyl hydrogen                                      3,4-dichlorophenyl    38  (S)-hydroxy                   (S)-phenyl hydrogen                                      3,4-difluorophenyl    39  (S)-hydroxy                   (S)-phenyl hydrogen                                      benzo b!-                                      thiophen-4-yl    40  (S)-hydroxy                   (S)-phenyl hydrogen                                      3,4-methylene-                                      dioxyphenyl    41  (S)-hydroxy                   (S)-phenyl hydrogen                                      3,5-difluorophenyl    42  (R)-tetrahydro-                   (S)-phenyl tetrahydro-                                      3,4-dichlorophenyl        pyranyloxy            pyranyl    43  (R)-hydroxy                   (S)-phenyl hydrogen                                      3,4-dichlorophenyl    44  (R)-hydroxy                   (R)-phenyl hydrogen                                      3,4-dichlorophenyl    45  (S)-methoxy-                   (S)-3-methyl-                              tetrahydro-                                      3,4-dichlorophenyl        methyloxy  phenyl     pyranyl    46  (S)-hydroxy                   (S)-3-methyl-                              hydrogen                                      3,4-dichlorophenyl                   phenyl    47  (S)-hydroxy                   (S)-4-chloro-                              hydrogen                                      3,4-dichlorophenyl                   phenyl    48  (S)-hydroxy                   (S)-4-     hydrogen                                      3,4-dichlorophenyl                   methoxy-                   phenyl    49  (S)-hydroxy                   (S)-4-     hydrogen                                      3,4-dichlorophenyl                   trifluoro-                   methylphenyl    50  (S)-hydroxyl                   (S)-4-methyl-                              hydrogen                                      3,4-dichlorophenyl                   phenyl    51  (S)-tetrahydro-                   (S)-3-     tetrahydro-                                      3,4-dichlorophenyl        pyranyloxy methoxy-   pyranyl                   methyloxy-                   phenyl    52  (S)-hydroxy                   (S)-3-     hydrogen                                      3,4-dichlorophenyl                   hydroxy-                   phenyl    ______________________________________

I claim:
 1. A compound of the following formula ##STR8## and a saltthereof wherein A is hydrogen, hydroxy or OY wherein Y is a hydroxyprotecting group selected from benzyl, triphenylmethyl,tetrahydropyrandyl, methoxymethyl and SiR1R2R3 wherein R¹, R² and R³ areeach C₁ -C₆ alkyl or phenyl;Ar is phenyl optionally substituted with oneor more substituent selected from halo, hydroxy, C₁ -C₄ alkyl, C₁ -C₄alkoxy, CF₃, C₁ -C₄ alkoxy-C₁ -C₄ alkyloxy and carboxy-C₁ -C₄ alkyloxy;X is phenyl, naphthyl, biphenyl, indanyl or 1-tetralone-6-yl, thesegroups optionally being substituted with up to three substituentsselected from halo, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, hydroxy, NO₂, CF₃ andSO₂ CH₃ ; and R is hydrogen, C₁ -C₄ alkyl or a hydroxy protecting groupselected from benzyl, triphenylmethyl, tetrahydropyranyl, methoxymethyland Si, R¹, R², R³ wherein R¹, R², R³ and each C₁ -C₆ alkyl or phenyl.2. A compound according to claim 1, wherein A is hydrogen or hydroxy,and R is hydrogen or C₁ -C₄ alkyl.
 3. A compound according to claim 2,wherein Ar is phenyl.
 4. A compound accorciing to claim 3, wherein X isphenyl substituted with up to three substituents selected from chloro,methyl and CF₃, and R is hydrogen.
 5. A compotinc according to claim 4,wherein X is 3,4-dichlorophenyl.
 6. A compound according to claim 4selected from 2-(3 ,4-Dichlorophenyl)-N-hydroxy-N-1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl!acetamide;N-Hydroxy-N-1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl!-2-(2,3,6-trichlorophenyl)acetamide;N-Hydroxy-N-1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl!-2-(4-trifluoromethylphenyl)acetamide;N-Hydroxy-N-1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl!-2-(2,4,6-trimethylphenyl)acetamide;2-(3,4-Dichlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide;2-(4-Bromophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide;N-Hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!-2-(4-trifluoromethylphenyl)acetamide;2-(4-Chlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide;2-(2,3-Dichlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide;2-(2,4-Dichlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide;2-(2,5-Dichlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide;2-(2,6-Dichlorophenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide;N-Hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!-2-(2,3,6-trichlorophenyl)acetamide;2-(3,4-Dichlorophenyl)-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide; and2-(3,4-Dimethylphenyl)-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl!acetamide.
 7. Acompound according to claim 1, wherein A is OY, and R is a hydroxyprotecting group, and wherein the hydroxy protecting groups are selectedfrom benzyl, triphenylmethyl, tetrahydropyranyl, methoxymethyl and R¹ R²R³ Si, wherein R¹,R² and R³ are each C₁ -C₆ alkyl or phenyl.
 8. Apharmaceutical composition useful as an analgesic, or an agent fortreatment of stroke or abdominal pain associated with functional boweldisease which comprises a compound according to claim 1, and apharmaceutically inert carrier.
 9. A method for the treatment of amedical condition for which agonist activity toward opioid Kappareceptor such as an analgesic is needed in a mammalian subject, themethod comprises administering to said subject a therapeuticallyeffective amount of a compound according to claim
 1. 10. A process forproducing a compound of the Formula (I), and the salt thereof whichcomprises reacting a compound of Formula ##STR9## wherein R is a hydroxyprotecting group selected from benzyl, tetrahydropyrinyl, methoxymethyl,triphenylmethyl, and R1 R2 R3Si wherein R1, R2 and R3 are each C1-C6alkyl or phenylA is hydrogen or hydroxy or OY wherein Y is selected frombenzyl riphenyl methyl, tetrahydropyranyl methoxymethyl and Si R1 R2 R3wherein R1, R2 and R3 are each C1-C6 alkyl or phenyl; with a carboxylicacid of the formula X CH2 COOH wherein X is phenyl naphtyl, biphenyl,indanyl or 1- tetralone-6-yl comprising coupling said carboxylic acidXCH2COOH with said formula II in the presence of a water solublecarbniimide; and removing the protecting group from the obtainedcompound by catalytic hydrogeration or acid-catalyzed hydrolysis andfollowed by base catalyzed alkylation using an alkylhalide in thepresence of a phase transfer catalyst.